Vatalanib (INN, codenamed PTK787 or PTK/ZK) is a small molecule protein kinase inhibitor that inhibits angiogenesis. It is being studied as a possible treatment for several types of cancer, particularly cancer that is at an advanced stage or has not responded to chemotherapy. Vatalanib is orally active, which is to say it is effective when taken by mouth.
Vatalanib is being developed by Bayer Schering and Novartis. It inhibits all known VEGF receptors, as well as platelet-derived growth factor receptor-beta and c-kit, but is most selective for VEGFR-2. |
Read full article at Wikipedia
|
InChI=1S/C20H15ClN4.C4H6O4/c21-15-5-7-16(8-6-15)23-20-18-4-2-1-3-17(18)19(24-25-20)13-14-9-11-22-12-10-14;5-3(6)1-2-4(7)8/h1-12H,13H2,(H,23,25);1-2H2,(H,5,6)(H,7,8) |
LLDWLPRYLVPDTG-UHFFFAOYSA-N |
C(CC(O)=O)C(O)=O.N1=NC(=C2C(=C1CC=3C=CN=CC3)C=CC=C2)NC4=CC=C(C=C4)Cl |
|
EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor
An EC 2.7.10.* (protein-tyrosine kinase) inhibitor that interferes with the action of receptor protein-tyrosine kinase (EC 2.7.10.1).
vascular endothelial growth factor receptor antagonist
An antagonist at the vascular endothelial growth factor receptor.
|
|
angiogenesis inhibitor
An agent and endogenous substances that antagonize or inhibit the development of new blood vessels.
antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
|
|
View more via ChEBI Ontology
CGP 79787D
|
ChemIDplus
|
PTK 787
|
ChemIDplus
|
PTK 787/ZK 222584
|
ChemIDplus
|
PTK-787
|
ChemIDplus
|
PTK787/ZK222584
|
ChemIDplus
|
vatalanib monosuccinate
|
ChEBI
|
ZK 222584
|
ChemIDplus
|
212142-18-2
|
CAS Registry Number
|
ChemIDplus
|
8664962
|
Reaxys Registry Number
|
Reaxys
|
Dragovich T, Laheru D, Dayyani F, Bolejack V, Smith L, Seng J, Burris H, Rosen P, Hidalgo M, Ritch P, Baker AF, Raghunand N, Crowley J, Von Hoff DD (2014) Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer chemotherapy and pharmacology 74, 379-387 [PubMed:24939212] [show Abstract]
PurposeVatalanib (PTK 787/ZK22584) is an oral poly-tyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy.MethodsVatalanib treatment consisted of a twice daily oral dosing using a "ramp-up schedule," beginning with 250 mg bid during week 1,500 mg bid during week 2, and 750 mg bid on week three and thereafter. The primary objective of this study was to evaluate the 6-month survival rate.ResultsSixty-seven patients were enrolled. The median age was 64, and 66% (N = 43) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20%; N = 13), fatigue (17%; N = 11), abdominal pain (17%; N = 11), and elevated alkaline phosphatase (15%; N = 10). Among the 65 evaluable patients, the 6-month survival rate was 29% (95% CI 18-41%) and the median progression-free survival was 2 months. Fifteen patients survived 6 months or more. Two patients had objective partial responses, and 28% of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug.ConclusionVatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls. | Raizer JJ, Grimm SA, Rademaker A, Chandler JP, Muro K, Helenowski I, Rice L, McCarthy K, Johnston SK, Mrugala MM, Chamberlain M (2014) A phase II trial of PTK787/ZK 222584 in recurrent or progressive radiation and surgery refractory meningiomas. Journal of neuro-oncology 117, 93-101 [PubMed:24449400] [show Abstract] When surgery and radiation are no longer treatment options, salvage systemic therapy has been used for recurrent meningiomas with little compelling evidence to suggest effectiveness. Patients with surgery and radiation refractory recurrent meningiomas were treated with the oral multifunctional tyrosine kinase inhibitor PTK787/ZK 222584 (PTK787) at a dose of 500 mg twice a day. Each treatment cycle was 4 weeks with MRI done every 8 weeks. Twenty-five patients (14 men; 11 women) with a median age of 59 years and KPS of 80 were treated. Meningioma WHO Grade was I in 2 patients, II in 14 patients and III in 8 patients; 1 patient had a hemangiopericytoma. All patients had prior surgery, external beam radiation therapy or radiosurgery and 11 patients prior systemic chemotherapy. Median number of cycles of PTK 787 administered was 4 (range <1-22). Best response in the 22 evaluable patients was stable disease in 15 (68.2 %). Predominant PTK787 related toxicities included fatigue (60 %), hypertension (24 %) and elevated transaminases (24 %). Grade II patients had a progression free survival (PFS)-6 of 64.3 %, a median PFS of 6.5 months and an overall survival (OS) of 26.0 months; grade III patients had a PFS-6 of 37.5 %, median PFS of 3.6 months and OS 23 months. PTK787 was modestly toxic at the dose of 500 mg administered twice per day. Activity as determined by PFS-6 suggests that targeting PDGF/VEGF pathway warrants further investigation. | Langenberg MH, Witteveen PO, Lankheet NA, Roodhart JM, Rosing H, van den Heuvel IJ, Beijnen JH, Voest EE (2010) Phase 1 study of combination treatment with PTK 787/ZK 222584 and cetuximab for patients with advanced solid tumors: safety, pharmacokinetics, pharmacodynamics analysis. Neoplasia (New York, N.Y.) 12, 206-213 [PubMed:20126478] [show Abstract]
IntroductionPTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically.MethodsIn phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m(2) weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed.ResultsSafety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months.ConclusionsThis study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity. | Hess-Stumpp H, Haberey M, Thierauch KH (2005) PTK 787/ZK 222584, a tyrosine kinase inhibitor of all known VEGF receptors, represses tumor growth with high efficacy. Chembiochem : a European journal of chemical biology 6, 550-557 [PubMed:15742376] [show Abstract] The angiogenesis inhibitor PTK 787/ZK 222584 (PTK/ZK) blocks all known VEGF receptor (VEGFR) tyrosine kinases, including the lymphangiogenic VEGFR3, in the lower nanomolar range. From a panel of 100 kinases only PDGFR, c-kit, and c-fms are inhibited beyond those in the nanomolar range. PTK/ZK functions as a competitive inhibitor at the ATP-binding site of the receptor kinase as shown here in kinetic experiments. The VEGF signal blockade in microvascular endothelial cells (MVEC) results in a blockade of MVEC proliferation (IC50=30 nM), without affecting the proliferation of normal tissue cells and tumor cells. The efficacy of PTK/ZK depends on its continuous presence within the endothelial target cells. Early removal attenuates its antiproliferative activity in vitro. Growth inhibition of endothelial cells is fully reversible as demonstrated by "washout" experiments. Without inhibiting tumor cell proliferation directly, PTK/ZK results in a significant retardation of tumor growth in a number of experimental tumor models of different tissue origin. Combination of PTK/ZK with an antiandrogen revealed additive effects on tumor-growth inhibition. Treatment efficacy was monitored both by tumor weight and by the determination of serum concentrations of the surrogate marker PSA. PTK/ZK is currently being investigated in patients with different solid tumor types for its therapeutic utility. Preliminary data from phase I/II clinical trials of PTK/ZK as a monotherapy suggested a positive safety and tolerability profile, which we interpret to be a consequence of the high selectivity of the drug for a limited number of kinases. Preliminary response, time to progression, and overall survival data were promising.1 Based on these encouraging results, PTK/ZK is currently in Phase III clinical trials for metastatic colorectal cancer. | Solorzano CC, Baker CH, Bruns CJ, Killion JJ, Ellis LM, Wood J, Fidler IJ (2001) Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Cancer biotherapy & radiopharmaceuticals 16, 359-370 [PubMed:11776753] [show Abstract] Since vascular endothelial growth factor (VEGF) plays a major role in tumor angiogenesis, we determined whether blockage of VEGF receptor signaling using a novel tyrosine kinase inhibitor (PTK 787) decreases the growth and metastasis of human pancreatic carcinoma growing orthotopically in nude mice. Human pancreatic L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice were given daily oral administrations of PTK 787 alone, twice weekly i.p. injections of gemcitabine, or combination therapy. The mice were necropsied when control mice became moribund (day 35). Therapy with PTK 787 alone, gemcitabine alone, or the combination of both agents produced respectively 60%, 70%, and 81% inhibition in the volume of pancreatic cancers. The combination therapy significantly decreased the incidence of lymph node and liver metastasis, leading to a significant increase in survival. Microvessel density (MVD) was significantly decreased in tumors treated with either PTK 787 alone or PTK 787 plus gemcitabine. MVD directly correlated with tumor cell proliferation and inversely correlated with apoptosis of tumor cells and associated endothelial cells. Collectively, our results demonstrate that blockade of VEGF-R signaling may provide an additional approach to the therapy of pancreatic cancer. | Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, Hofmann F, Mestan J, Mett H, O'Reilly T, Persohn E, Rösel J, Schnell C, Stover D, Theuer A, Towbin H, Wenger F, Woods-Cook K, Menrad A, Siemeister G, Schirner M, Thierauch KH, Schneider MR, Drevs J, Martiny-Baron G, Totzke F (2000) PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer research 60, 2178-2189 [PubMed:10786682] [show Abstract] PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role. |
|