6312-00-1Relevant articles and documents
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, Gianluca,Posteri, Helena,Borghi, Daniela,Busel, Alina A.,Caprera, Francesco,Casale, Elena,Ciomei, Marina,Cirla, Alessandra,Corti, Emiliana,D'Anello, Matteo,Fasolini, Marina,Forte, Barbara,Galvani, Arturo,Isacchi, Antonella,Khvat, Alexander,Krasavin, Mikhail Y.,Lupi, Rosita,Orsini, Paolo,Perego, Rita,Pesenti, Enrico,Pezzetta, Daniele,Rainoldi, Sonia,Riccardi-Sirtori, Federico,Scolaro, Alessandra,Sola, Francesco,Zuccotto, Fabio,Felder, Eduard R.,Donati, Daniele,Montagnoli, Alessia
, p. 6875 - 6898 (2015/09/22)
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.
