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

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 <i>BRCA2</i>-functional cancer cells to PARP inhibitors. Starting from compound <b>1</b>, a phenyl furan-carboxyquinoline, we developed a series of analogues, leading to derivative <b>19</b>. 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, <b>19</b> 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.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2026-01-26
DOI
https://doi.org/10.1021/acsmedchemlett.5c00711
Primary Topic
PARP inhibition in cancer therapy
Type
article
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article

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

Marina Belloni Veronesi, Marinella Roberti, Stefania Girotto, Andrea Cavalli et al.
ACS Medicinal Chemistry Letters
PARP inhibition in cancer therapy
article

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

Marina Belloni Veronesi, Marinella Roberti, Stefania Girotto, Andrea Cavalli, Laura Poppi, Greta Bagnolini, Federico Falchi, Mirco Masi, Viola Previtali, Giuseppina Di Stefano, Giulia Varignani, Giovanni Ferrandi, Francesca Franco, Angela Andonaia
article en

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 <i>BRCA2</i>-functional cancer cells to PARP inhibitors. Starting from compound <b>1</b>, a phenyl furan-carboxyquinoline, we developed a series of analogues, leading to derivative <b>19</b>. 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, <b>19</b> 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.

ACS Medicinal Chemistry LettersVol. 17(2)
Italian Institute of Technology (IT), Institute of Biophysics (BG), Computational Physics (United States) (US), Teikoku Pharma (United States) (US), École Polytechnique Fédérale de Lausanne (CH), University of Bologna (IT)
Good health and well-being
Openalex Percentile: Top 77%
PARP inhibition in cancer therapy
DOIOpen Access PDFOpenAlex
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