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

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.