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. Epub 2015 Aug 26.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biological Availability
  • Cell Proliferation / drug effects
  • Dacarbazine / administration & dosage
  • Dacarbazine / analogs & derivatives
  • Drug Screening Assays, Antitumor
  • Female
  • Heterografts
  • High-Throughput Screening Assays
  • Humans
  • Isoindoles / administration & dosage
  • Isoindoles / chemistry*
  • Isoindoles / pharmacology
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / pathology
  • Piperidines / administration & dosage
  • Piperidines / chemistry*
  • Piperidines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Temozolomide
  • Triple Negative Breast Neoplasms

Substances

  • Antineoplastic Agents
  • Isoindoles
  • NMS-P118
  • Piperidines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Dacarbazine
  • Temozolomide

Associated data

  • PDB/4ZZX
  • PDB/4ZZY
  • PDB/4ZZZ
  • PDB/5A00