Synthetic Lethality in Pancreatic Cancer: Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits Homologous Recombination and Synergizes with Olaparib

J Med Chem. 2020 Mar 12;63(5):2588-2619. doi: 10.1021/acs.jmedchem.9b01526. Epub 2020 Feb 24.

Abstract

Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism*
  • Cell Line, Tumor
  • DNA Damage / drug effects
  • Drug Discovery
  • Drug Synergism
  • Homologous Recombination / drug effects
  • Humans
  • Models, Molecular
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Phthalazines / chemistry
  • Phthalazines / pharmacology*
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Protein Interaction Maps / drug effects
  • Rad51 Recombinase / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Synthetic Lethal Mutations / drug effects

Substances

  • Antineoplastic Agents
  • BRCA2 Protein
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Small Molecule Libraries
  • Rad51 Recombinase
  • olaparib