# Targeting RAD51-BRCA2 Interaction to Enhance Synthetic Lethality with Olaparib in Pancreatic Cancer: Development of a Novel Phenyl Furan-Quinoline-Carboxylic Acid Series

## TL;DR

This paper introduces a new compound that enhances the effectiveness of olaparib in pancreatic cancer by targeting a specific protein interaction.

## Contribution

The study presents a novel phenyl furan-quinoline-carboxylic acid derivative that induces synthetic lethality in pancreatic cancer cells.

## Key findings

- Compound 19 inhibits RAD51-BRCA2 interaction and impairs homologous recombination.
- Compound 19 synergizes with olaparib in BxPC-3 pancreatic cancer cells in 2D and 3D models.
- Compound 19 shows efficacy in human pancreatic cancer cells without toxicity to normal cells.

## Abstract

Synthetic lethality
has proven to be a tactical paradigm to design
synergistic anticancer drug combinations. In this context, we leveraged
BRCA2 and PARP as a synthetic lethal target pair to consolidate the
use of small molecule inhibitors of RAD51-BRCA2 protein–protein
interaction as inducers of the BRCAness phenotype that sensitizes BRCA2-functional cancer cells to PARP inhibitors. Starting
from compound 1, a phenyl furan-carboxyquinoline, we
developed a series of analogues, leading to derivative 19. This compound effectively inhibits RAD51-BRCA2 interaction, impairs
homologous recombination, and synergizes with olaparib in BxPC-3 pancreatic
cancer cells, inducing synthetic lethality in both 2D and 3D spheroids.
Additionally, 19 showed efficacy in human pancreatic
cancer cells and no toxicity in normal pancreatic cells, positioning
it as an early tool compound and a starting point for further optimization.