TY - JOUR
T1 - Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118)
T2 - a potent, orally available, and highly selective PARP-1 inhibitor for cancer therapy
AU - Papeo, Gianluca
AU - Posteri, Helena
AU - Borghi, Daniela
AU - Busel, Alina A.
AU - Caprera, Francesco
AU - Casale, Elena
AU - Ciomei, Marina
AU - Cirla, Alessandra
AU - Corti, Emiliana
AU - D'Anello, Matteo
AU - Fasolini, Marina
AU - Forte, Barbara
AU - Galvani, Arturo
AU - Isacchi, Antonella
AU - Khvat, Alexander
AU - Krasavin, Mikhail Y.
AU - Lupi, Rosita
AU - Orsini, Paolo
AU - Perego, Rita
AU - Pesenti, Enrico
AU - Pezzetta, Daniele
AU - Rainoldi, Sonia
AU - Riccardi-Sirtori, Federico
AU - Scolaro, Alessandra
AU - Sola, Francesco
AU - Zuccotto, Fabio
AU - Felder, Eduard R.
AU - Donati, Daniele
AU - Montagnoli, Alessia
PY - 2015/9/10
Y1 - 2015/9/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84941551184&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.5b00680
DO - 10.1021/acs.jmedchem.5b00680
M3 - Article
C2 - 26222319
AN - SCOPUS:84941551184
SN - 0022-2623
VL - 58
SP - 6875
EP - 6898
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -
