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

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 - https://www.scopus.com/pages/publications/84941551184

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 -