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| rucaparib |
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| CHEBI:134689 |
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| A member of the class of azepinoindoles that is 1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one carrying additional 4-[(methylamino)methyl]phenyl and fluoro substituents at positions 2 and 8 respectively. It is an inhibitor of poly (ADP-ribose) polymerase and is used (as the camsylate salt) as monotherapy for advanced ovarian cancer and deleterious germline or somatic BRCA mutation. |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:94311
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| ChemicalBook:CB51475507, ZINC000000025958 |
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more structures >>
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call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__482633087277822__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__482633087277822__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI%3ACHEBI%3A94311","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__482633087277822__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"482633087277822","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__482633087277822__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol RPB - Ideal conformer RDKit 3D starting HoverWatcher_5 Time for openFile(RPB - Ideal conformer RDKit 3D 42 45 0 0 0 0 0 0 0 0999 V2000 -4.6520 2.0580 0.9130 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.6260 1.8000 0.3120 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.8550 2.8400 -0.0600 N 0 0 0 0 0 0 0 0 0 0 0 0 -1.6460 2.6750 -0.8280 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.5390 1.9810 -0.0740 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.7440 0.5100 0.0070 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.0220 -0.1130 0.0240 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.3380 0.3880 0.0630 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.3930 -0.5070 -0.1310 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.1480 -1.8620 -0.2580 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.1810 -2.7090 -0.4620 F 0 0 0 0 0 0 0 0 0 0 0 0 -2.8610 -2.3630 -0.1800 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.7940 -1.4980 -0.0360 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.4330 -1.6940 0.0750 N 0 0 0 0 0 0 0 0 0 0 0 0 0.1910 -0.4680 0.0830 C 0 0 0 0 0 0 0 0 0 0 0 0 1.6510 -0.2510 0.1610 C 0 0 0 0 0 0 0 0 0 0 0 0 2.4190 -0.9730 1.0760 C 0 0 0 0 0 0 0 0 0 0 0 0 3.7810 -0.7660 1.1440 C 0 0 0 0 0 0 0 0 0 0 0 0 2.2690 0.6710 -0.6850 C 0 0 0 0 0 0 0 0 0 0 0 0 3.6320 0.8690 -0.6070 C 0 0 0 0 0 0 0 0 0 0 0 0 4.3860 0.1540 0.3070 C 0 0 0 0 0 0 0 0 0 0 0 0 5.8750 0.3750 0.3870 C 0 0 0 0 0 0 0 0 0 0 0 0 6.5560 -0.5440 -0.5340 N 0 0 0 0 0 0 0 0 0 0 0 0 8.0130 -0.3570 -0.4830 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.1240 3.7350 0.1980 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.8770 2.0930 -1.7210 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2930 3.6580 -1.1390 H 0 0 0 0 0 0 0 0 0 0 0 0 0.4080 2.1790 -0.5760 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.4930 2.3870 0.9370 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.4070 -0.1370 -0.1810 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.6920 -3.4280 -0.2390 H 0 0 0 0 0 0 0 0 0 0 0 0 0.0110 -2.5550 0.1370 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9470 -1.6910 1.7300 H 0 0 0 0 0 0 0 0 0 0 0 0 1.6810 1.2290 -1.3990 H 0 0 0 0 0 0 0 0 0 0 0 0 4.3760 -1.3230 1.8520 H 0 0 0 0 0 0 0 0 0 0 0 0 4.1120 1.5820 -1.2610 H 0 0 0 0 0 0 0 0 0 0 0 0 6.1050 1.4040 0.1090 H 0 0 0 0 0 0 0 0 0 0 0 0 6.2160 0.1890 1.4050 H 0 0 0 0 0 0 0 0 0 0 0 0 6.3080 -1.5020 -0.3380 H 0 0 0 0 0 0 0 0 0 0 0 0 8.4920 -1.0500 -1.1750 H 0 0 0 0 0 0 0 0 0 0 0 0 8.2580 0.6660 -0.7670 H 0 0 0 0 0 0 0 0 0 0 0 0 8.3680 -0.5490 0.5290 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 2 3 1 0 2 8 1 0 3 4 1 0 4 5 1 0 5 6 1 0 6 7 1 0 6 15 2 0 7 8 2 0 7 13 1 0 8 9 1 0 9 10 2 0 10 11 1 0 10 12 1 0 12 13 2 0 13 14 1 0 14 15 1 0 15 16 1 0 16 17 2 0 16 19 1 0 17 18 1 0 18 21 2 0 19 20 2 0 20 21 1 0 21 22 1 0 22 23 1 0 23 24 1 0 3 25 1 0 4 26 1 0 4 27 1 0 5 28 1 0 5 29 1 0 9 30 1 0 12 31 1 0 14 32 1 0 17 33 1 0 19 34 1 0 18 35 1 0 20 36 1 0 22 37 1 0 22 38 1 0 23 39 1 0 24 40 1 0 24 41 1 0 24 42 1 0 M END): 15 ms reading 42 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. 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| Rucaparib, sold under the brand name Rubraca, is a PARP inhibitor used as an anti-cancer agent. Rucaparib is a first-in-class pharmaceutical drug targeting the DNA repair enzyme poly-ADP ribose polymerase-1 (PARP-1). It is taken by mouth.
The most common side effects include tiredness or weakness, nausea (feeling sick), increased levels of creatinine (which may indicate kidney problems) and liver enzymes in the blood (which may indicate liver damage), vomiting, anaemia (low red blood cell counts), decreased appetite, dysgeusia (taste disturbances), diarrhoea, thrombocytopenia (low levels of platelets) and abdominal pain (belly ache).
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Read full article at Wikipedia
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InChI=1S/C19H18FN3O/c1- 21-10-11-2-4-12(5-3-11)18-14-6-7-22-19(24)15-8-13(20)9-16(23-18)17(14)15/h2-5,8-9,21,23H,6-7,10H2,1H3,(H,22,24) |
| HMABYWSNWIZPAG-UHFFFAOYSA-N |
| CNCC1=CC=C(C=C1)C1=C2CCNC(=O)C3=C2C(N1)=CC(F)=C3 |
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor
An EC 2.4.2.* (pentosyltransferase) inhibitor that interferes with the action of a NAD+ ADP-ribosyltransferase (EC 2.4.2.30).
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antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
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View more via ChEBI Ontology
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8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one
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rucaparib
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WHO MedNet
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rucaparib
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WHO MedNet
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rucaparib
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WHO MedNet
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rucaparibum
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WHO MedNet
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11556434
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Reaxys Registry Number
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Reaxys
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283173-50-2
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CAS Registry Number
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KEGG DRUG
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283173-50-2
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CAS Registry Number
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ChemIDplus
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Li S, Li XY, Zhang TJ, Zhu J, Liu KL, Wang DP, Meng FH (2021)
Novel 4,5-dihydrospiro[benzo[c]azepine-1,1'-cyclohexan]-3(2H)-one derivatives as PARP-1 inhibitors: Design, synthesis and biological evaluation.
Bioorganic chemistry 111, 104840 [PubMed:33780687]
[show Abstract]
To further explore the research of novel PARP-1 inhibitors, we designed and synthesized a series of novel amide PARP-1 inhibitors based on our previous research. Most compounds displayed certain antitumor activities against four tumor cell lines (A549, HepG2, HCT-116, and MCF-7). Specifically, the candidate compound R8e possessed strong anti-proliferative potency toward A549 cells with the IC50 value of 2.01 μM. Compound R8e had low toxicity to lung cancer cell line. And the in vitro enzyme inhibitory activity of compound R8e was better than rucaparib. Molecular docking studies provided a rational binding model of compound R8e in complex with rucaparib. The following cell cycle and apoptosis assays revealed that compound R8e could arrest cell cycle in the S phase and induce cell apoptosis. Western blot analysis further showed that compound R8e could effectively inhibit the PAR's biosynthesis and was more effective than rucaparib. Overall, based on the biological activity evaluation, compound R8e could be a potential lead compound for further developing novel amide PARP-1 inhibitors. | Cho HY, Kim YB, Park WH, No JH (2021)
Enhanced Efficacy of Combined Therapy with Checkpoint Kinase 1 Inhibitor and Rucaparib via Regulation of Rad51 Expression in BRCA Wild-Type Epithelial Ovarian Cancer Cells.
Cancer research and treatment 53, 819-828 [PubMed:33332934]
[show Abstract]
PurposeThis study aimed to evaluate anticancer effects of combination treatment with poly(ADP-ribose) polymerase (PARP) and checkpoint kinase 1 (Chk1) inhibitors in BRCA wild-type ovarian cancer. PARP inhibitors can function as DNA-damaging agents in BRCA wild-type cancer, even if clinical activity is limited. Most epithelial ovarian cancers are characterized by a TP53 mutation causing dysfunction at the G1/S checkpoint, which makes tumor cells highly dependent on Chk1-mediated G/M phase cell-cycle arrest for DNA repair.Materials and methodsWe investigated the anticancer effects of combination treatment with prexasertib (LY2606368), a selective ATP competitive small molecule inhibitor of Chk1 and Chk2, and rucaparib, a PARP inhibitor, in BRCA wild-type ovarian cancer cell lines (OVCAR3 and SKOV3).ResultsWe found that combined treatment significantly decreased cell viability in all cell lines and induced greater DNA damage and apoptosis than in the control and/or using monotherapies. Moreover, we found that prexasertib significantly inhibited homologous recombination-mediated DNA repair and thus showed a marked anticancer effect in combination treatment with rucaparib. The anticancer mechanism of prexasertib and rucaparib was considered to be caused by an impaired G2/M checkpoint due to prexasertib treatment, which forced mitotic catastrophe in the presence of rucaparib.ConclusionOur results suggest a novel effective therapeutic strategy for BRCA wild-type epithelial ovarian cancer using a combination of Chk1 and PARP inhibitors. | Konecny GE, Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, Ray-Coquard I, Aghajanian C, Coleman RL, O'Malley DM, Leary A, Chen LM, Provencher D, Ma L, Brenton JD, Castro C, Green M, Simmons AD, Beltman J, Harding T, Lin KK, Lin KK, Goble S, Maloney L, Kristeleit RS, McNeish IA, Swisher EM, Xiao JJ (2021)
Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2.
Gynecologic oncology 161, 668-675 [PubMed:33752918]
[show Abstract]
ObjectiveTo evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2.MethodsEfficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model.ResultsRucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05).ConclusionThe exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma. | Lorusso D, Maltese G, Sabatucci I, Cresta S, Matteo C, Ceruti T, D'Incalci M, Zucchetti M, Raspagliesi F, Sonetto C, Sinno V, Ronzulli D, Giolitto S, de Braud F (2021)
Phase I Study of Rucaparib in Combination with Bevacizumab in Ovarian Cancer Patients: Maximum Tolerated Dose and Pharmacokinetic Profile.
Targeted oncology 16, 59-68 [PubMed:33369704]
[show Abstract]
BackgroundTargeted agents, such as antiangiogenic drugs (e.g., bevacizumab) and poly(ADP-ribose) polymerase inhibitors (e.g., rucaparib), have been shown to improve outcomes in patients with newly diagnosed or recurrent ovarian cancer. Evidence suggests that combinations of these two classes of targeted agents may result in synergistic antitumor activity.ObjectiveThe phase I portion of MITO 25 was designed to determine the maximum tolerated dose, pharmacokinetics, and the safety profile of rucaparib when administered in combination with bevacizumab as maintenance treatment for patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer.MethodsThis was a single-arm, phase I dose-escalation study. Cohorts of three patients were recruited to receive increasing rucaparib doses of 400 mg, 500 mg, or 600 mg twice daily for 28 days. Bevacizumab 15 mg/kg was administered at day 1 every 21 days.ResultsWe enrolled nine patients. Two patients in the rucaparib 600-mg group had four grade 3 treatment-emergent adverse events: increased in alanine aminotransferase and aspartate aminotransferase levels, depression, and hallucinations. These were deemed to be dose-limiting toxicities related to rucaparib. Because these dose-limiting toxicities occurred in the 600-mg group and affected more than one in three patients, the maximum tolerated dose for rucaparib was considered 500 mg twice daily when combined with bevacizumab 15 mg/kg at day 1 every 21 days. There were no new safety concerns from using the combination. No substantial difference in pharmacokinetic parameters was found between the cohorts or in the pharmacokinetic profiles of rucaparib administered alone or with bevacizumab with respect to historical controls.ConclusionsThe maximum tolerated dose of rucaparib is 500 mg twice daily when co-administered with bevacizumab. The plasma concentration-time profiles of rucaparib in combination with bevacizumab suggest no pharmacokinetic interactions between the drugs. The randomized phase II portion of MITO 25 will further investigate rucaparib maintenance treatment with or without bevacizumab in patients with newly diagnosed stage III-IV ovarian cancer who responded to carboplatin-paclitaxel chemotherapy with or without bevacizumab.Trial registrationClinicalTrials.gov identifier NCT03462212; registered March 2018. | Fennell DA, King A, Mohammed S, Branson A, Brookes C, Darlison L, Dawson AG, Gaba A, Hutka M, Morgan B, Nicholson A, Richards C, Wells-Jordan P, Murphy GJ, Thomas A, MiST1 study group (2021)
Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial.
The Lancet. Respiratory medicine 9, 593-600 [PubMed:33515503]
[show Abstract]
BackgroundMalignant mesothelioma remains an incurable cancer, with no effective treatments in the setting of relapsed disease. Homologous recombination deficiency predicts sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. In mesothelioma, BRCA1-associated protein 1 carboxy-terminal hydrolase (BAP1), which regulates DNA repair, is frequently mutated. We aimed to test the hypothesis that BAP1-deficient or BRCA1-deficient mesotheliomas would be sensitive to PARP inhibition by rucaparib.MethodsWe did a single-centre, open-label, single-arm, phase 2a trial in Leicester, UK, with prospective molecular stratification (Mesothelioma-Stratified Therapy 1 [MiST1]). Patients aged 18 years or older who had radiologically progressing, histologically confirmed, malignant mesothelioma after at least one course of systemic treatment; with cytoplasmic-BAP1-deficient or BRCA1-deficient mesothelioma (pleural or peritoneal or other primary localisation), and who met the other inclusion criteria, were deemed eligible. All eligible patients who consented to take part were given rucaparib 600 mg twice a day orally, for six cycles of 28 days, or until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response was measured by CT scan every 6 weeks. The primary outcome was disease control (complete response, partial response, or stable disease) at 12 weeks in all patients who received study drug; secondary outcomes were the safety and toxicity profile, objective response rate (proportion of complete or partial responses), and disease control rate at 24 weeks. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03654833.FindingsBetween Feb 9 and June 10, 2019, we enrolled 26 molecularly and clinically eligible patients. Ten (38%) of 26 patients were BAP1 negative and BRCA1 negative, 23 patients (89%) were BAP1 negative, and 13 patients (50%) were BRCA1 negative. Disease control rate at 12 weeks was 58% (95% CI 37-77; 15 of 26 patients), and at 24 weeks was 23% (9-44; six of 26 patients). Rucaparib was well tolerated, with 15 (9%) of 166 adverse events being grade 3 or 4, which were seen in nine (35%) of 26 patients, and there were no deaths. The most common grade 1-2 adverse events were nausea (18 [69%] of 26 patients), fatigue (14 patients [54%]), and decreased appetite (ten patients [38%]). The most common grade 3-4 adverse events were upper respiratory tract infection (three patients [12%]) and anaemia (three patients [12%]). All six cycles of rucaparib were received by eight (31%) of 26 patients. One or more dose reductions occurred in nine patients (35%).InterpretationRucaparib in patients with BAP1-negative or BRCA1-negative mesothelioma met the prespecified criteria for success, showing promising activity with manageable toxicity. Further investigation of homologous recombination deficiency mutations is planned to refine the identification of predictive biomarkers for PARP inhibition in mesothelioma.FundingUniversity of Leicester (Leicester, UK), Asthma UK and British Lung Foundation Partnership, and the Victor Dahdaleh Foundation (Toronto, ON, Canada). | Anscher MS, Chang E, Gao X, Gong Y, Weinstock C, Bloomquist E, Adeniyi O, Charlab R, Zimmerman S, Serlemitsos-Day M, Ning YM, Mayrosh R, Fuller B, Trentacosti AM, Gallagher P, Bijwaard K, Philip R, Ghosh S, Fahnbulleh F, Diggs F, Arora S, Goldberg KB, Tang S, Amiri-Kordestani L, Pazdur R, Ibrahim A, Beaver JA (2021)
FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA-Mutated Metastatic Castrate-Resistant Prostate Cancer.
The oncologist 26, 139-146 [PubMed:33145877]
[show Abstract]
The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open-label single-arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%-57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty-six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly-(ADP-ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3-4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. IMPLICATIONS FOR PRACTICE: The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single-arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug. | Curtin NJ (2020)
The Development of Rucaparib/Rubraca®: A Story of the Synergy Between Science and Serendipity.
Cancers 12, E564 [PubMed:32121331]
[show Abstract]
The poly(ADP-ribose) polymerase (PARP) inhibitor, Rubraca®, was given its first accelerated approval for BRCA-mutated ovarian cancer by the FDA at the end of 2016, and further approval by the FDA, EMA and NICE followed. Scientists at Newcastle University initiated the early stages, and several collaborations with scientists in academia and the pharmaceutical industry enabled its final development to the approval stage. Although originally considered as a chemo- or radiosensitiser, its current application is as a single agent exploiting tumour-specific defects in DNA repair. As well as involving intellectual and physical effort, there have been a series of fortuitous occurrences and coincidences of timing that ensured its success. This review describes the history of the relationship between science and serendipity that brought us to the current position. | Hanson RL, Batchelor E (2020)
Rucaparib Treatment Alters p53 Oscillations in Single Cells to Enhance DNA-Double-Strand-Break-Induced Cell Cycle Arrest.
Cell reports 33, 108240 [PubMed:33053351]
[show Abstract]
DNA double strand breaks induce oscillatory expression of the transcription factor p53 that is dependent on ataxia telangiectasia mutated (ATM) activity and the rate of double strand break resolution. Although p53 dynamics are known to play a role in the regulation of cell fate determination, the consequences of the variability in dynamics associated with differences in repair rates and utilized repair pathways are unknown. Using single-cell time-lapse microscopy, we found that disruption of specific repair pathways has distinct impacts on p53 dynamics. The small-molecule rucaparib, an inhibitor of the alternative end-joining-associated protein poly (ADP-ribose) polymerase (PARP), increased p53 pulse duration, altering the temporal expression of multiple p53 target genes. As a result, combination treatments of the radiomimetic drug neocarzinostatin with rucaparib drove prolonged growth arrest beyond that of DNA damage alone. This study highlights how pharmacological manipulation of DNA repair pathways may be used to alter p53 dynamics to enhance therapeutic regimens. | Chen Z, Ling K, Zhu Y, Deng L, Li Y, Liang Z (2020)
Rucaparib antagonize multidrug resistance in cervical cancer cells through blocking the function of ABC transporters.
Gene 759, 145000 [PubMed:32717310]
[show Abstract]
Upregulation of the ATP-binding cassette (ABC) transporter is one of the most important factors leading to multidrug resistance (MDR) in several types of cancer. In the present study, we investigated the ability of rucaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor which is currently in clinical development, on overcoming ABC transporters-mediated MDR in cervical cancer cell lines. Rucaparib significantly enhanced the cytotoxic effects of a series of conventional chemotherapeutic drugs in drug resistance cervical cancer cell lines. Moreover, rucaparib significantly increased the accumulation of rhodamine 123 in doxorubicin- and paclitaxel-resistance cervical cancer cell lines. In addition, rucaparib significantly increased the accumulation of tritium-labeled chemotherapeutic drugs in drug resistance cervical cancer cells, and decrease the efflux of tritium-labeled chemotherapeutic drugs. Molecular docking study indicated that rucaparib could bind to the active site of the ABC transporters. The present study indicated that rucaparib could antagonize MDR in cervical cancer cells by blocking the function of ABC transporters. The results obtained in the present study provide the potential possibilities that the combination of rucaparib with other chemotherapeutic agents may benefit patients with cervical cancer. | Wolford JE, Bai J, Moore KN, Kristeleit R, Monk BJ, Tewari KS (2020)
Cost-effectiveness of niraparib, rucaparib, and olaparib for treatment of platinum-resistant, recurrent ovarian carcinoma.
Gynecologic oncology 157, 500-507 [PubMed:32173049]
[show Abstract]
BackgroundOlaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease.MethodsMedian progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non‑platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations.ResultsNon‑platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non‑platinum-based regimens.ConclusionHigh costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care. | Abida W, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, Sautois B, Vogelzang NJ, Bambury RM, Voog E, Zhang J, Piulats JM, Ryan CJ, Merseburger AS, Daugaard G, Heidenreich A, Fizazi K, Higano CS, Krieger LE, Sternberg CN, Watkins SP, Despain D, Simmons AD, Loehr A, Dowson M, Golsorkhi T, Chowdhury S, TRITON2 investigators (2020)
Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38, 3763-3772 [PubMed:32795228]
[show Abstract]
PurposeBRCA1 or BRCA2 (BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study.MethodsWe enrolled patients who progressed after one to two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate.ResultsEfficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients).ConclusionRucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types. | Zandarashvili L, Langelier MF, Velagapudi UK, Hancock MA, Steffen JD, Billur R, Hannan ZM, Wicks AJ, Krastev DB, Pettitt SJ, Lord CJ, Talele TT, Pascal JM, Black BE (2020)
Structural basis for allosteric PARP-1 retention on DNA breaks.
Science (New York, N.Y.) 368, eaax6367 [PubMed:32241924]
[show Abstract]
The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable. | Lorusso D, García-Donas J, Sehouli J, Joly F (2020)
Management of Adverse Events During Rucaparib Treatment for Relapsed Ovarian Cancer: A Review of Published Studies and Practical Guidance.
Targeted oncology 15, 391-406 [PubMed:32495160]
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The poly(ADP-ribose) polymerase inhibitor rucaparib is approved as monotherapy in the treatment and maintenance settings for women with relapsed ovarian cancer in the European Union and the United States. We review the safety profile of rucaparib in both settings and provide recommendations for the clinical management of the main adverse events (AEs) that may occur during rucaparib treatment. We searched PubMed and congress proceedings for safety data on oral rucaparib monotherapy (600 mg twice daily) from clinical trials involving patients with relapsed ovarian cancer. AE management guidance was developed from clinical trial protocols, rucaparib prescribing information, oncology association guidelines, and author experience. The most frequent any-grade treatment-emergent AEs (TEAEs) included gastrointestinal symptoms, asthenia/fatigue, dysgeusia, anemia/decreased hemoglobin, and increased alanine/aspartate aminotransferase. Across clinical trials, 61.8% of patients had one or more grade 3 or higher TEAEs. Clinicians should employ close follow-up for TEAEs, particularly early in treatment, and educate patients about expected TEAEs and methods for their monitoring and management (e.g., antiemetics for nausea/vomiting, transfusions for hematologic TEAEs, or dose interruptions/reductions for moderate/severe TEAEs). Overall, 16.2% of patients discontinued rucaparib due to TEAEs. Management of AEs that may occur during rucaparib treatment is crucial for patients to obtain optimal clinical benefit by remaining on therapy and to avoid their detrimental impact on quality of life. | Colomba E, Pautier P, Pommeret F, Leary A (2019)
Rucaparib in the landscape of PARP inhibition in ovarian cancer.
Expert review of anticancer therapy 19, 437-446 [PubMed:30977683]
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Introduction: The landscape of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer is rapidly evolving and becoming increasingly complex. Ovarian cancer is leading therapeutic innovation by providing the proof of concept for DNA repair as a target. Three different PARP inhibitors have now received approvals in the US and Europe in different indications. Subtle but crucial differences can be found among the licensed indications for each PARP inhibitor in terms of histology, type of BRCA mutation (germline and/or somatic), number of prior lines of chemotherapy and whether the indication is in the treatment or maintenance settings. Areas covered: We review the latest clinical data regarding the PARP inhibitor rucaparib in ovarian cancer, provide an update on the evolving landscape of PARP inhibition in ovarian cancer, and summarize avenues of ongoing and future research. Expert opinion: All eligible patients should be offered a PARP inhibitor. SOLO1 trial results demonstrated an unprecedented benefit maintenance with PARP inhibitors in first line. Results from trials evaluating PARP inhibitors as maintenance in first line regardless of BRCA status and from trials evaluating combinatorial strategies are eagerly awaited. | Redelico T (2019)
Rucaparib and Niraparib in Advanced Ovarian Cancer.
Journal of the advanced practitioner in oncology 10, 402-408 [PubMed:33343988]
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Rucaparib and niraparib are two of the newest U.S. Food and Drug Administration-approved PARP inhibitors, joining olaparib with indications in ovarian cancer. Both drugs have led to meaningful responses when used as monotherapy in previously treated ovarian cancers, with niraparib demonstrating activity in both BRCA-mutated and BRCA wild-type tumors. Both rucaparib and niraparib have remarkably increased progression-free survival as maintenance therapy for patients with relapsed, platinum-sensitive epithelial ovarian cancer who responded to their most recent platinum-based regimen. In this setting, these drugs appear to be similar in efficacy but have distinct pharmacokinetic and adverse effect profiles. This article will guide the advanced practitioner through the efficacy, safety, and pharmacologic profiles of rucaparib and niraparib, while benchmarking them against olaparib for the treatment of ovarian cancer. | Shirley M (2019)
Rucaparib: A Review in Ovarian Cancer.
Targeted oncology 14, 237-246 [PubMed:30830551]
[show Abstract]
Rucaparib (Rubraca®) is a small molecule poly(ADP-ribose) polymerase (PARP) inhibitor with potent activity against PARP-1, -2 and -3. It is approved in the USA and the EU for the treatment of adult patients with BRCA-mutated ovarian cancer who have been treated with two or more lines of chemotherapy. Rucaparib is also approved in the USA and the EU for use as maintenance therapy in adult patients with recurrent or relapsed ovarian cancer who are in a complete or partial response to platinum-based chemotherapy. Based on an analysis of patients across two phase II clinical trials, rucaparib displayed clinical activity as third- (or later-) line treatment of BRCA-mutated ovarian cancer, with rucaparib-treated patients having a confirmed objective response rate of 54%. Furthermore, as demonstrated in the randomized, placebo-controlled, phase III ARIEL3 trial, rucaparib significantly improved progression-free survival when used as maintenance treatment in patients with platinum-sensitive ovarian cancer. Rucaparib had an acceptable tolerability profile in clinical trials in women with ovarian cancer. Common adverse events were generally manageable with dose modification and/or supportive care. Thus, currently available data indicate that rucaparib is a useful addition to the options available to clinicians for the treatment of advanced ovarian cancer, in both the treatment and maintenance therapy settings. | (2017)
Rucaparib Approved for Ovarian Cancer.
Cancer discovery 7, 120-121 [PubMed:28057616]
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The FDA approved the PARP inhibitor rucaparib to treat women with advanced ovarian cancer who have already been treated with at least two chemotherapies and have a BRCA1 or BRCA2 gene mutation identified by an approved companion diagnostic test. The agency also gave a nod to the FoundationFocus CDxBRCA test to detect BRCA alterations. | McCormick A, Donoghue P, Dixon M, O'Sullivan R, O'Donnell RL, Murray J, Kaufmann A, Curtin NJ, Edmondson RJ (2017)
Ovarian Cancers Harbor Defects in Nonhomologous End Joining Resulting in Resistance to Rucaparib.
Clinical cancer research : an official journal of the American Association for Cancer Research 23, 2050-2060 [PubMed:27702817]
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Purpose: DNA damage defects are common in ovarian cancer and can be used to stratify treatment. Although most work has focused on homologous recombination (HR), DNA double-strand breaks are repaired primarily by nonhomologous end joining (NHEJ). Defects in NHEJ have been shown to contribute to genomic instability and have been associated with the development of chemoresistance.Experimental Design: NHEJ was assessed in a panel of ovarian cancer cell lines and 47 primary ascetic-derived ovarian cancer cultures, by measuring the ability of cell extracts to end-join linearized plasmid monomers into multimers. mRNA and protein expression of components of NHEJ was determined using RT-qPCR and Western blotting. Cytotoxicities of cisplatin and the PARP inhibitor rucaparib were assessed using sulforhodamine B (SRB) assays. HR function was assessed using γH2AX/RAD51 foci assay.Results: NHEJ was defective (D) in four of six cell lines and 20 of 47 primary cultures. NHEJ function was independent of HR competence (C). NHEJD cultures were resistant to rucaparib (P = 0.0022). When HR and NHEJ functions were taken into account, only NHEJC/HRD cultures were sensitive to rucaparib (compared with NHEJC/HRC P = 0.034, NHEJD/HRC P = 0.0002, and NHEJD/HRD P = 0.0045). The DNA-PK inhibitor, NU7441, induced resistance to rucaparib (P = 0.014) and HR function recovery in a BRCA1-defective cell line.Conclusions: This study has shown that NHEJ is defective in 40% of ovarian cancers, which is independent of HR function and associated with resistance to PARP inhibitors in ex vivo primary cultures. Clin Cancer Res; 23(8); 2050-60. ©2016 AACR. | Cardillo TM, Sharkey RM, Rossi DL, Arrojo R, Mostafa AA, Goldenberg DM (2017)
Synthetic Lethality Exploitation by an Anti-Trop-2-SN-38 Antibody-Drug Conjugate, IMMU-132, Plus PARP Inhibitors in BRCA1/2-wild-type Triple-Negative Breast Cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research 23, 3405-3415 [PubMed:28069724]
[show Abstract]
Purpose: Both PARP inhibitors (PARPi) and sacituzumab govitecan (IMMU-132) are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)-inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC.Experimental Design:In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, double-stranded DNA (dsDNA) breaks, and cell-cycle arrest. Mice bearing BRCA1/2-mutated or -wild-type human TNBC tumor xenografts were treated with the combination of IMMU-132 and PARPi (olaparib or talazoparib). Study survival endpoint was tumor progression to >1.0 cm3 and tolerability assessed by hematologic changes.Results: Combining IMMU-132 in TNBC with all three different PARPi results in synergistic growth inhibition, increased dsDNA breaks, and accumulation of cells in the S-phase of the cell cycle, regardless of BRCA1/2 status. A combination of IMMU-132 plus olaparib or talazoparib produces significantly improved antitumor effects and delay in time-to-tumor progression compared with monotherapy in mice bearing BRCA1/2-mutated HCC1806 TNBC tumors. Furthermore, in mice bearing BRCA1/2-wild-type tumors (MDA-MB-468 or MDA-MB-231), the combination of IMMU-132 plus olaparib imparts a significant antitumor effect and survival benefit above that achieved with monotherapy. Most importantly, this combination was well tolerated, with no substantial changes in hematologic parameters.Conclusions: These data demonstrate the added benefit of combining Topo I inhibition mediated by IMMU-132 with synthetic lethality provided by PARPi in TNBC, regardless of BRCA1/2 status, thus supporting the rationale for such a combination clinically. Clin Cancer Res; 23(13); 3405-15. ©2017 AACR. | Rae C, Mairs RJ (2017)
Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells.
International journal of radiation biology 93, 194-203 [PubMed:27600766]
[show Abstract]
PurposeDespite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. Although ionizing radiation is used to treat localized and metastatic prostate cancer, the most efficient use of radiotherapy is yet to be defined. Our purpose was to determine in vitro the potential benefit to be gained by combining radiation treatment with cytotoxic drugs.Materials and methodsInhibitors of DNA repair and heat shock protein 90 and an inducer of oxidative stress were evaluated in combination with X-radiation for their capacity to reduce clonogenic survival and delay the growth of multicellular tumor spheroids.ResultsInhibitors of the PARP DNA repair pathway, olaparib and rucaparib, and the HSP90 inhibitor 17-DMAG, enhanced the clonogenic cell kill and spheroid growth delay induced by X-radiation. However, the oxidative stress-inducing drug elesclomol failed to potentiate the effects of X-radiation. PARP inhibitors arrested cells in the G2/M phase when administered as single agents or in combination with radiation, whereas elesclomol and 17-DMAG did not affect radiation-induced cell cycle modulation.ConclusionThese results indicate that radiotherapy of prostate cancer may be optimized by combination with inhibitors of PARP or HSP90, but not elesclomol. | Thorsell AG, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L, Moche M, Cohen MS, Schüler H (2017)
Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
Journal of medicinal chemistry 60, 1262-1271 [PubMed:28001384]
[show Abstract]
Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects. | Knepper TC, Saller J, Walko CM (2017)
Novel and Expanded Oncology Drug Approvals of 2016-PART 1: New Options in Solid Tumor Management.
Oncology (Williston Park, N.Y.) 31, 110-121 [PubMed:28205191]
[show Abstract]
The nonradiologic medical management of solid tumors has evolved from the use of traditional cytotoxic agents to modern targeted therapies, monoclonal antibodies, and immunotherapies. Advances in the understanding of cancer biology and therapeutic strategies have resulted in increasing numbers of new drug applications and approvals. Consequently, practicing oncologists need to learn how the newly available agents function and what toxicities to watch for, as well as ways to optimize the use of both new drugs and previously approved drugs with new indications. In 2016, the US Food and Drug Administration approved three novel drugs for the treatment of solid malignancies-olaratumab in selected patients with soft-tissue sarcoma, atezolizumab for the treatment of bladder cancer, and rucaparib for the treatment of ovarian cancer; also in 2016, the use of previously approved anticancer agents (including atezolizumab) was expanded into 11 new patient populations. The diversity of options for patients is evident in the broad range of the 2016 approvals, which include immune checkpoint inhibitors, targeted therapies, monoclonal antibodies, and traditional cytotoxic agents. This article focuses on the new agents and indications that emerged in 2016 for solid tumor treatment. We review the drug indications, mechanisms of action, pivotal trial data, pertinent toxicities, use in special populations, and the appropriate clinical contexts for treatment planning. | Dockery LE, Gunderson CC, Moore KN (2017)
Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer.
OncoTargets and therapy 10, 3029-3037 [PubMed:28790837]
[show Abstract]
Rucaparib camsylate (CO-338, AG-014699, PF-01367338) is a potent PARP-1, PARP-2, and PARP-3 inhibitor. Phase I and II studies demonstrated clinical efficacy in both BRCA-mutated (inclusive of germline and somatic) ovarian tumors and ovarian tumors with homologous recombination deficiency (HRD) loss of heterozygosity (LOH). Rucaparib has received the US Food and Drug Administration (FDA) approval for patients with deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer who have been treated with two or more chemotherapies. There is evidence to suggest that rucaparib has clinical efficacy against ovarian tumors with high HRD-LOH. Rucaparib's companion diagnostic FoundationFocus™ CDx BRCA test is the first FDA-approved next-generation sequencing-based companion diagnostic test designed to identify patients likely to respond to rucaparib. This article reviews the mechanisms of action, safety, approval, and indications for use of the PARP inhibitor rucaparib as well as future trials and use of rucaparib's companion diagnostic test. | Swisher EM, Lin KK, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, Konecny GE, Coleman RL, Tinker AV, O'Malley DM, Kristeleit RS, Ma L, Bell-McGuinn KM, Brenton JD, Cragun JM, Oaknin A, Ray-Coquard I, Harrell MI, Mann E, Kaufmann SH, Floquet A, Leary A, Harding TC, Goble S, Maloney L, Isaacson J, Allen AR, Rolfe L, Yelensky R, Raponi M, McNeish IA (2017)
Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.
The Lancet. Oncology 18, 75-87 [PubMed:27908594]
[show Abstract]
BackgroundPoly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor.MethodsARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing.Findings256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8-10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0-14·7) in the BRCA mutant subgroup, 5·7 months (5·3-7·6) in the LOH high subgroup, and 5·2 months (3·6-5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high (0·62, 0·42-0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 [22%] patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 [12%]). Common serious adverse events included small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anaemia (nine [4%]). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred.InterpretationIn patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours.FundingClovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award. | Nile DL, Rae C, Hyndman IJ, Gaze MN, Mairs RJ (2016)
An evaluation in vitro of PARP-1 inhibitors, rucaparib and olaparib, as radiosensitisers for the treatment of neuroblastoma.
BMC cancer 16, 621 [PubMed:27515310]
[show Abstract]
BackgroundThe radiopharmaceutical (131)I-meta-iodobenzylguanidine ((131)I-MIBG) is an effective treatment for neuroblastoma. However, maximal therapeutic benefit from (131)I-MIBG is likely to be obtained by its combination with chemotherapy. We previously reported enhanced antitumour efficacy of (131)I-MIBG by inhibition of the poly(ADP-ribose) polymerase-1 (PARP-1) DNA repair pathway using the phenanthridinone derivative PJ34. Recently developed alternative PARP-1 inhibitors have greater target specificity and are expected to be associated with reduced toxicity to normal tissue. Therefore, our purpose was to determine whether the more specific PARP-1 inhibitors rucaparib and olaparib enhanced the efficacy of X-radiation or (131)I-MIBG.MethodsRadiosensitisation of SK-N-BE(2c) neuroblastoma cells or noradrenaline transporter gene-transfected glioma cells (UVW/NAT) was investigated using clonogenic assay. Propidium iodide staining and flow cytometry was used to analyse cell cycle progression. DNA damage was quantified by the phosphorylation of H2AX (γH2AX).ResultsBy combining PARP-1 inhibition with radiation treatment, it was possible to reduce the X-radiation dose or (131)I-MIBG activity concentration required to achieve 50 % cell kill by approximately 50 %. Rucaparib and olaparib were equally effective inhibitors of PARP-1 activity. X-radiation-induced DNA damage was significantly increased 2 h after irradiation by combination with PARP-1 inhibitors (10-fold greater DNA damage compared to untreated controls; p < 0.01). Moreover, combination treatment (i) prevented the restitution of DNA, exemplified by the persistence of 3-fold greater DNA damage after 24 h, compared to untreated controls (p < 0.01) and (ii) induced greater G2/M arrest (p < 0.05) than either single agent alone.ConclusionRucaparib and olaparib sensitise cancer cells to X-radiation or (131)I-MIBG treatment. It is likely that the mechanism of radiosensitisation entails the accumulation of unrepaired radiation-induced DNA damage. Our findings suggest that the administration of PARP-1 inhibitors and (131)I-MIBG to high risk neuroblastoma patients may be beneficial. | Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley M, Jayson G, Sludden J, Murray J, Jamieson D, Halford S, Acton G, Backholer Z, Mangano R, Boddy A, Curtin N, Plummer R (2016)
Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer.
British journal of cancer 114, 723-730 [PubMed:27002934]
[show Abstract]
BackgroundRucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers.MethodsPhase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0-1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles.ResultsRucaparib was well tolerated in patients up to doses of 480 mg per day and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, with a median duration of response of 179 days (range 84-567 days).ConclusionsRucaparib is well tolerated and results in high levels of PARP inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is active in gBRCA-mutant ovarian cancer and this activity correlates with platinum-free interval. The key lessons learned from this study is that continuous rucaparib dosing is required for optimal response, the recommended phase 2 dose (RP2D) for continuous oral scheduling has not been established and requires further exploration and, thirdly, the use of a PD biomarker to evaluate dose-response has its limitations. | Vaidyanathan A, Sawers L, Gannon AL, Chakravarty P, Scott AL, Bray SE, Ferguson MJ, Smith G (2016)
ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells.
British journal of cancer 115, 431-441 [PubMed:27415012]
[show Abstract]
BackgroundClinical response to chemotherapy for ovarian cancer is frequently compromised by the development of drug-resistant disease. The underlying molecular mechanisms and implications for prescription of routinely prescribed chemotherapy drugs are poorly understood.MethodsWe created novel A2780-derived ovarian cancer cell lines resistant to paclitaxel and olaparib following continuous incremental drug selection. MTT assays were used to assess chemosensitivity to paclitaxel and olaparib in drug-sensitive and drug-resistant cells±the ABCB1 inhibitors verapamil and elacridar and cross-resistance to cisplatin, carboplatin, doxorubicin, rucaparib, veliparib and AZD2461. ABCB1 expression was assessed by qRT-PCR, copy number, western blotting and immunohistochemical analysis and ABCB1 activity assessed by the Vybrant and P-glycoprotein-Glo assays.ResultsPaclitaxel-resistant cells were cross-resistant to olaparib, doxorubicin and rucaparib but not to veliparib or AZD2461. Resistance correlated with increased ABCB1 expression and was reversible following treatment with the ABCB1 inhibitors verapamil and elacridar. Active efflux of paclitaxel, olaparib, doxorubicin and rucaparib was confirmed in drug-resistant cells and in ABCB1-expressing bacterial membranes.ConclusionsWe describe a common ABCB1-mediated mechanism of paclitaxel and olaparib resistance in ovarian cancer cells. Optimal choice of PARP inhibitor may therefore limit the progression of drug-resistant disease, while routine prescription of first-line paclitaxel may significantly limit subsequent chemotherapy options in ovarian cancer patients. | Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley M, Jayson G, Sludden J, Murray J, Jamieson D, Halford S, Acton G, Backholer Z, Mangano R, Boddy A, Curtin N, Plummer R (2016)
Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer.
British journal of cancer 114, e21 [PubMed:27228289] | Knezevic CE, Wright G, Rix LLR, Kim W, Kuenzi BM, Luo Y, Watters JM, Koomen JM, Haura EB, Monteiro AN, Radu C, Lawrence HR, Rix U (2016)
Proteome-wide Profiling of Clinical PARP Inhibitors Reveals Compound-Specific Secondary Targets.
Cell chemical biology 23, 1490-1503 [PubMed:27866910]
[show Abstract]
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we generated a comparative proteome-wide target map of the four clinical PARPi, olaparib, veliparib, niraparib, and rucaparib. PARPi as a class displayed high target selectivity. However, in addition to the canonical targets PARP1, PARP2, and several of their binding partners, we also identified hexose-6-phosphate dehydrogenase (H6PD) and deoxycytidine kinase (DCK) as previously unrecognized targets of rucaparib and niraparib, respectively. Subsequent functional validation suggested that inhibition of DCK by niraparib could have detrimental effects when combined with nucleoside analog pro-drugs. H6PD silencing can cause apoptosis and further sensitize cells to PARPi, suggesting that H6PD may be, in addition to its established role in metabolic disorders, a new anticancer target. | Jenner ZB, Sood AK, Coleman RL (2016)
Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy.
Future oncology (London, England) 12, 1439-1456 [PubMed:27087632]
[show Abstract]
Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy. Comparable to rucaparib development, other PARP inhibitors, such as olaparib, niraparib, veliparib and talazoparib, are developing CDx tests for targeted therapy. PARP inhibitor clinical trials and CDx assays are discussed in this review, as are potential PARP inhibitor combination therapies and likely resistance mechanisms. | McLachlan J, George A, Banerjee S (2016)
The current status of PARP inhibitors in ovarian cancer.
Tumori 102, 433-440 [PubMed:27716873]
[show Abstract]
Recent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach. Importantly, companion homologous recombination deficiency scores are being developed to help guide the selection of patients most likely to gain clinical benefit from PARP inhibition. Olaparib, the first and most extensively investigated PARP inhibitor, is now licensed in Europe for maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated (germline or somatic) high-grade serous ovarian cancer who have responded to platinum-based chemotherapy. In the United States, olaparib is licensed for treatment of patients with germline BRCA-mutated ovarian cancer who have received 3 or more lines of chemotherapy. There are a number of other PARP inhibitors in late phase clinical development in ovarian cancer including rucaparib, niraparib, veliparib, and talazoparib. This review will focus on the current evidence for PARP inhibitors in ovarian cancer and discuss ongoing clinical trials and future research directions in this rapidly evolving area. | Wang DD, Li C, Sun W, Zhang S, Shalinsky DR, Kern KA, Curtin NJ, Sam WJ, Kirkpatrick TR, Plummer R (2015)
PARP activity in peripheral blood lymphocytes as a predictive biomarker for PARP inhibition in tumor tissues - A population pharmacokinetic/pharmacodynamic analysis of rucaparib.
Clinical pharmacology in drug development 4, 89-98 [PubMed:27128213]
[show Abstract]
PurposeRucaparib is a potent Poly (ADP-ribose) Polymerase (PARP) inhibitor currently under clinical development. The objectives of this analysis were to establish population PK and PK/PD models for rucaparib, and to evaluate the predictability of PARP activity in PBL for PARP activity in tumor tissues.Experimental designRucaparib concentrations and PARP activity in human PBLs and tumor issues were obtained from 32 patients with solid tumors in a Phase 1 First-in-Patient study. Simulations were conducted to evaluate different dosing regimens.ResultsA 3-compartment PK model best described the PK of rucaparib. An Emax model best described the exposure and PARP inhibition relationship. The maximum PARP inhibition (Imax) achieved in PBLs and in tumors were 90.9% and 90.0% of the baseline PARP activity, and the IC50 values were 1.05 ng/mL and 1.10 ng/mL, respectively. PAR polymer baseline value was found to be a covariate of Emin.ConclusionPopulation PK and PK/PD models have been established to describe population PK of rucaparib and the relationship between rucaparib plasma concentration and PARP inhibition in both PBLs and tumor issues. Results from this trial indicated that PARP inhibition in PBLs can be used as a substitute for PARP inhibition in melanoma tumor tissues. | Parrish KE, Cen L, Murray J, Calligaris D, Kizilbash S, Mittapalli RK, Carlson BL, Schroeder MA, Sludden J, Boddy AV, Agar NY, Curtin NJ, Elmquist WF, Sarkaria JN (2015)
Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System.
Molecular cancer therapeutics 14, 2735-2743 [PubMed:26438157]
[show Abstract]
PARP inhibition can enhance the efficacy of temozolomide and prolong survival in orthotopic glioblastoma (GBM) xenografts. The aim of this study was to evaluate the combination of the PARP inhibitor rucaparib with temozolomide and to correlate pharmacokinetic and pharmacodynamic studies with efficacy in patient-derived GBM xenograft models. The combination of rucaparib with temozolomide was highly effective in vitro in short-term explant cultures derived from GBM12, and, similarly, the combination of rucaparib and temozolomide (dosed for 5 days every 28 days for 3 cycles) significantly prolonged the time to tumor regrowth by 40% in heterotopic xenografts. In contrast, the addition of rucaparib had no impact on the efficacy of temozolomide in GBM12 or GBM39 orthotopic models. Using Madin-Darby canine kidney (MDCK) II cells stably expressing murine BCRP1 or human MDR1, cell accumulation studies demonstrated that rucaparib is transported by both transporters. Consistent with the influence of these efflux pumps on central nervous system drug distribution, Mdr1a/b(-/-)Bcrp1(-/-) knockout mice had a significantly higher brain to plasma ratio for rucaparib (1.61 ± 0.25) than wild-type mice (0.11 ± 0.08). A pharmacokinetic and pharmacodynamic evaluation after a single dose confirmed limited accumulation of rucaparib in the brain is associated with substantial residual PARP enzymatic activity. Similarly, matrix-assisted laser desorption/ionization mass spectrometric imaging demonstrated significantly enhanced accumulation of drug in flank tumor compared with normal brain or orthotopic tumors. Collectively, these results suggest that limited drug delivery into brain tumors may significantly limit the efficacy of rucaparib combined with temozolomide in GBM. | McCrudden CM, O'Rourke MG, Cherry KE, Yuen HF, O'Rourke D, Babur M, Telfer BA, Thomas HD, Keane P, Nambirajan T, Hagan C, O'Sullivan JM, Shaw C, Williams KJ, Curtin NJ, Hirst DG, Robson T (2015)
Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself.
PloS one 10, e0118187 [PubMed:25689628]
[show Abstract]
Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation. | Haikarainen T, Narwal M, Joensuu P, Lehtiö L (2014)
Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors.
ACS medicinal chemistry letters 5, 18-22 [PubMed:24900770]
[show Abstract]
Tankyrases, an enzyme subfamily of human poly(ADP-ribosyl)polymerases, are potential drug targets especially against cancer. We have evaluated inhibition of tankyrases by known PARP inhibitors and report five cocrystal structures of the most potent compounds in complex with human tankyrase 2. The inhibitors include the small general PARP inhibitors Phenanthridinone, PJ-34, and TIQ-A as well as the more advanced inhibitors EB-47 and rucaparib. The compounds anchor to the nicotinamide subsite of tankyrase 2. Crystal structures reveal flexibility of the ligand binding site with implications for drug development against tankyrases and other ADP-ribosyltransferases. EB-47 mimics the substrate NAD(+) and extends from the nicotinamide to the adenosine subsite. The clinical ARTD1 inhibitor candidate rucaparib was the most potent tankyrase inhibitor identified (24 and 14 nM for tankyrases), which indicates that inhibition of tankyrases would affect the cellular responses of this compound. |
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