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

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

  • ACS Med Chem Lett. 2026 Jan 26;17(2):520-530. doi: 10.1021/acsmedchemlett.5c00711.
Giovanni Ferrandi 1 2,  Greta Bagnolini 1,  Laura Poppi 2,  Mirco Masi 2,  Viola Previtali 2,  Angela Andonaia 2,  Giulia Varignani 1 2,  Marina Veronesi 3,  Francesca De Franco 4,  Federico Falchi 1 2,  Giuseppina Di Stefano 5,  Stefania Girotto 3,  Marinella Roberti 1,  Andrea Cavalli 1 2 6
Affiliations

Affiliations

  • 1 Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
  • 2 Computational and Chemical Biology, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
  • 3 Structural Biophysics Facility, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
  • 4 TES Pharma S.r.l., I-06073 Corciano, Perugia, Italy.
  • 5 Department of Medical and Surgical Sciences, University of Bologna,40126 Bologna, Italy.
  • 6 Centre Européen de Calcul Atomique et Moléculaire (CECAM), Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
PMID: 41704388 DOI: 10.1021/acsmedchemlett.5c00711
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.

Keywords

RAD51-BRCA2; Synthetic lethality; pancreatic cancer; protein−protein interaction inhibitors; small molecules.

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