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Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.

Papeo G, Posteri H, Borghi D, Busel AA, Caprera F, Casale E, Ciomei M, Cirla A, Corti E, D'Anello M, Fasolini M, Forte B, Galvani A, Isacchi A, Khvat A, Krasavin MY, Lupi R, Orsini P, Perego R, Pesenti E, Pezzetta D, Rainoldi S, Riccardi-Sirtori F, Scolaro A, Sola F, Zuccotto F, Felder ER, Donati D, Montagnoli A
J Med Chem 58 6875-98 (2015)
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Cited: 53 times
EuropePMC logo PMID: 26222319

Abstract

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

Articles - 4zzz mentioned but not cited (15)

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  12. Altering Nitrogen Heterocycles of AZD2461 Affords High Affinity Poly(ADP-ribose) Polymerase-1 Inhibitors with Decreased P-Glycoprotein Interactions. Reilly SW, Puentes LN, Hsieh CJ, Makvandi M, Mach RH. ACS Omega 3 9997-10001 (2018)
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  2. PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling. van Beek L, McClay É, Patel S, Schimpl M, Spagnolo L, Maia de Oliveira T. Int J Mol Sci 22 5112 (2021)
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  3. AutoGrow4: an open-source genetic algorithm for de novo drug design and lead optimization. Spiegel JO, Durrant JD. J Cheminform 12 25 (2020)
  4. Bridging of nucleosome-proximal DNA double-strand breaks by PARP2 enhances its interaction with HPF1. Gaullier G, Roberts G, Muthurajan UM, Bowerman S, Rudolph J, Mahadevan J, Jha A, Rae PS, Luger K. PLoS One 15 e0240932 (2020)
  5. A ribose-functionalized NAD+ with unexpected high activity and selectivity for protein poly-ADP-ribosylation. Zhang XN, Cheng Q, Chen J, Lam AT, Lu Y, Dai Z, Pei H, Evdokimov NM, Louie SG, Zhang Y. Nat Commun 10 4196 (2019)
  6. Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy. Yuan Z, Chen S, Sun Q, Wang N, Li D, Miao S, Gao C, Chen Y, Tan C, Jiang Y. Bioorg Med Chem 25 4100-4109 (2017)
  7. Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy. Chang X, Sun D, Shi D, Wang G, Chen Y, Zhang K, Tan H, Liu J, Liu B, Ouyang L. Acta Pharm Sin B 11 156-180 (2021)
  8. Autonomous molecule generation using reinforcement learning and docking to develop potential novel inhibitors. Jeon W, Kim D. Sci Rep 10 22104 (2020)
  9. Identification and Characterization of MortaparibPlus-A Novel Triazole Derivative That Targets Mortalin-p53 Interaction and Inhibits Cancer-Cell Proliferation by Wild-Type p53-Dependent and -Independent Mechanisms. Sari AN, Elwakeel A, Dhanjal JK, Kumar V, Sundar D, Kaul SC, Wadhwa R. Cancers (Basel) 13 835 (2021)
  10. Anticancer potential of diarylidenyl piperidone derivatives, HO-4200 and H-4318, in cisplatin resistant primary ovarian cancer. ElNaggar AC, Saini U, Naidu S, Wanner R, Sudhakar M, Fowler J, Nagane M, Kuppusamy P, Cohn DE, Selvendiran K. Cancer Biol Ther 17 1107-1115 (2016)
  11. Chemical Proteomics Approach for Profiling the NAD Interactome. Šileikytė J, Sundalam S, David LL, Cohen MS. J Am Chem Soc 143 6787-6791 (2021)
  12. Discovery of 2-substituted 1H-benzo[d]immidazole-4-carboxamide derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors with in vivo anti-tumor activity. Zhou J, Ji M, Zhu Z, Cao R, Chen X, Xu B. Eur J Med Chem 132 26-41 (2017)
  13. Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515. Papeo G, Orsini P, Avanzi NR, Borghi D, Casale E, Ciomei M, Cirla A, Desperati V, Donati D, Felder ER, Galvani A, Guanci M, Isacchi A, Posteri H, Rainoldi S, Riccardi-Sirtori F, Scolaro A, Montagnoli A. ACS Med Chem Lett 10 534-538 (2019)
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  15. Molecular Mechanism of Selective Binding of NMS-P118 to PARP-1 and PARP-2: A Computational Perspective. Wang R, Cong Y, Li M, Bao J, Qi Y, Zhang JZH. Front Mol Biosci 7 50 (2020)
  16. Targeting on poly(ADP-ribose) polymerase activity with DNA-damaging hybrid lactam-steroid alkylators in wild-type and BRCA1-mutated ovarian cancer cells. Trafalis DT, Polonifi A, Dalezis P, Nikoleousakos N, Katsamakas S, Sarli V. Chem Biol Drug Des 90 854-866 (2017)
  17. Pharmacophore based design of some multi-targeted compounds targeted against pathways of diabetic complications. Chadha N, Silakari O. J Mol Graph Model 76 412-418 (2017)
  18. Comparative computational and experimental analyses of some natural small molecules to restore transcriptional activation function of p53 in cancer cells harbouring wild type and p53Ser46 mutant. Shefrin S, Sari AN, Kumar V, Zhang H, Meidinna HN, Kaul SC, Wadhwa R, Sundar D. Curr Res Struct Biol 4 320-331 (2022)
  19. Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors. Zhao H, Ji M, Cui G, Zhou J, Lai F, Chen X, Xu B. Bioorg Med Chem 25 4045-4054 (2017)
  20. A multi-task FP-GNN framework enables accurate prediction of selective PARP inhibitors. Ai D, Wu J, Cai H, Zhao D, Chen Y, Wei J, Xu J, Zhang J, Wang L. Front Pharmacol 13 971369 (2022)
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  22. Chiral bifunctional organocatalysts for enantioselective synthesis of 3-substituted isoindolinones. Hu XM, Zhang R, Dong H, Jia YY, Bao GQ, Wang PA. RSC Adv 13 24460-24465 (2023)
  23. Design and Synthesis of Novel Pyridine-Based Compounds as Potential PIM-1 Kinase Inhibitors, Apoptosis, and Autophagy Inducers Targeting MCF-7 Cell Lines: In Vitro and In Vivo Studies. Shaban SM, Eltamany EH, Boraei ATA, Nafie MS, Gad EM. ACS Omega 8 46922-46933 (2023)
  24. Rapid Ring-Opening Metathesis Polymerization of Monomers Obtained from Biomass-Derived Furfuryl Amines and Maleic Anhydride. Blanpain A, Clark JH, Farmer TJ, Guo Y, Ingram IDV, Kendrick JE, Lawrenson SB, North M, Rodgers G, Whitwood AC. ChemSusChem 12 2393-2401 (2019)
  25. Revealing the selective mechanisms of inhibitors to PARP-1 and PARP-2 via multiple computational methods. Hu H, Chen B, Zheng D, Huang G. PeerJ 8 e9241 (2020)
  26. Synthesis of New Bioactive Indolyl-1,2,4-Triazole Hybrids As Dual Inhibitors for EGFR/PARP-1 Targeting Breast and Liver Cancer Cells. Youssef MF, Nafie MS, Salama EE, Boraei ATA, Gad EM. ACS Omega 7 45665-45677 (2022)


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