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
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- 作者：Gianluca Papeo ; Helena Posteri ; Daniela Borghi ; Alina A. Busel ; Francesco Caprera ; Elena Casale ; Marina Ciomei ; Alessandra Cirla ; Emiliana Corti ; Matteo D鈥橝nello ; Marina Fasolini ; Barbara Forte ; Arturo Galvani ; Antonella Isacchi ; Alexander Khvat ; Mikhail Y. Krasavin ; Rosita Lupi ; Paolo Orsini ; Rita Perego ; Enrico Pesenti ; Daniele Pezzetta ; Sonia Rainoldi ; Federico Riccardi-Sirtori ; Alessandra Scolaro ; Francesco Sola ; Fabio Zuccotto ; Eduard R. Felder ; Daniele Donati ; Alessia Montagnoli
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：September 10, 2015
- 年：2015
- 卷：58
- 期：17
- 页码：6875-6898
- 全文大小：954K
- ISSN：1520-4804
文摘
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.