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Synthetic Lethality in Pancreatic Cancer: Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits

Greta Bagnolini1,2, Domenico Milano1, Marcella Manerba1

  • 1Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.

Journal of Medicinal Chemistry
|February 11, 2020
PubMed

Insights

Researchers developed a novel small molecule that mimics BRCA2 mutations to induce synthetic lethality in pancreatic cancer. This approach enhances the efficacy of PARP inhibitors (PARPi) in treating resistant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Synthetic lethality offers a promising strategy for developing novel anticancer drugs.
  • Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective in treating cancers with BRCA mutations.
  • Pancreatic cancer remains a significant unmet need in oncology.

Purpose of the Study:

  • To explore a new paradigm of fully small-molecule-induced synthetic lethality.
  • To identify novel therapeutic strategies for pancreatic cancer.
  • To target the RAD51-BRCA2 protein-protein interaction.

Main Methods:

  • Discovery of a dihydroquinolone pyrazoline-based molecule (35d).
  • Assessment of 35d's effect on RAD51-BRCA2 interaction and homologous recombination.
  • Evaluation of 35d's synergy with olaparib (a PARPi) in pancreatic cancer cells.

Main Results:

  • Molecule 35d disrupts the RAD51-BRCA2 protein-protein interaction, mimicking BRCA2 deficiency.
  • 35d inhibits homologous recombination in a human pancreatic adenocarcinoma cell line.
  • 35d exhibits synthetic lethality with olaparib in pancreatic cancer cells.

Conclusions:

  • Fully small-molecule-induced synthetic lethality is a viable strategy for targeting pancreatic cancer.
  • This approach can potentially broaden the application of PARPi to BRCA-competent and olaparib-resistant cancers.
  • The identified molecule 35d represents a novel therapeutic candidate for unmet oncological needs.

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