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

Gianluca Papeo (Lead / Corresponding author), Helena Posteri, Daniela Borghi, Alina A. Busel, Francesco Caprera, Elena Casale, Marina Ciomei, Alessandra Cirla, Emiliana Corti, Matteo D'Anello, Marina Fasolini, Barbara Forte, Arturo Galvani, Antonella Isacchi, Alexander Khvat, Mikhail Y. Krasavin, Rosita Lupi, Paolo Orsini, Rita Perego, Enrico PesentiDaniele Pezzetta, Sonia Rainoldi, Federico Riccardi-Sirtori, Alessandra Scolaro, Francesco Sola, Fabio Zuccotto, Eduard R. Felder, Daniele Donati, Alessia Montagnoli

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6875-6898
Number of pages24
JournalJournal of Medicinal Chemistry
Volume58
Issue number17
DOIs
Publication statusPublished - 10 Sep 2015

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