Q1 · MEDICINE
Article
Author: Lupi, Rosita ; Ciomei, Marina ; Caprera, Francesco ; Forte, Barbara ; Montagnoli, Alessia ; D’Anello, Matteo ; Galvani, Arturo ; Cirla, Alessandra ; Borghi, Daniela ; Posteri, Helena ; Corti, Emiliana ; Pezzetta, Daniele ; Krasavin, Mikhail Y. ; Zuccotto, Fabio ; Casale, Elena ; Fasolini, Marina ; Perego, Rita ; Orsini, Paolo ; Donati, Daniele ; Rainoldi, Sonia ; Pesenti, Enrico ; Isacchi, Antonella ; Busel, Alina A. ; Felder, Eduard R. ; Papeo, Gianluca ; Scolaro, Alessandra ; Sola, Francesco ; Khvat, Alexander ; Riccardi-Sirtori, Federico
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.