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

  • J Med Chem. 2015 Sep 10;58(17):6875-98. doi: 10.1021/acs.jmedchem.5b00680.
Gianluca Papeo  1 ,  Helena Posteri  1 ,  Daniela Borghi  1 ,  Alina A Busel  2 ,  Francesco Caprera  1 ,  Elena Casale  1 ,  Marina Ciomei  1 ,  Alessandra Cirla  1 ,  Emiliana Corti  1 ,  Matteo D'Anello  1 ,  Marina Fasolini  1 ,  Barbara Forte  1 ,  Arturo Galvani  1 ,  Antonella Isacchi  1 ,  Alexander Khvat  2 ,  Mikhail Y Krasavin  2 ,  Rosita Lupi  1 ,  Paolo Orsini  1 ,  Rita Perego  1 ,  Enrico Pesenti  1 ,  Daniele Pezzetta  3 ,  Sonia Rainoldi  1 ,  Federico Riccardi-Sirtori  1 ,  Alessandra Scolaro  1 ,  Francesco Sola  1 ,  Fabio Zuccotto  1 ,  Eduard R Felder  1 ,  Daniele Donati  1 ,  Alessia Montagnoli  1
Affiliations
  • 1. Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
  • 2. Chemical Diversity Research Institute , Rabochaya St. 2 Khimki, Moscow Region 114401, Russia.
  • 3. Accelera Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
PMID: 26222319 DOI: 10.1021/acs.jmedchem.5b00680
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18954
    NMS-P118
    99.54%, PARP-1 Inhibitor
    target: PARP
    Research Areas: Cancer