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

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

  • J Med Chem. 2020 Mar 12;63(5):2588-2619. doi: 10.1021/acs.jmedchem.9b01526.
Greta Bagnolini 1 2,  Domenico Milano 1,  Marcella Manerba 1,  Fabrizio Schipani 1,  Jose Antonio Ortega 1,  Dario Gioia 1,  Federico Falchi 1,  Andrea Balboni 1 2,  Fulvia Farabegoli 2,  Francesca De Franco 3,  Janet Robertson 3,  Roberto Pellicciari 3,  Isabella Pallavicini 4,  Sebastiano Peri 4,  Saverio Minucci 5 4,  Stefania Girotto 1,  Giuseppina Di Stefano 6,  Marinella Roberti 2,  Andrea Cavalli 1 2
Affiliations

Affiliations

  • 1 Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • 2 Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
  • 3 TES Pharma S.r.l., Via Palmiro Togliatti 22bis, I-06073 Corciano, Perugia, Italy.
  • 4 Department of Experimental Oncology at the IEO, European Institute of Oncology IRCCS, IFOM-IEO Campus, Via Adamello 16, 20100 Milan, Italy.
  • 5 Department of Biosciences, University of Milan, Via Celoria 26, 20100 Milan, Italy.
  • 6 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy.
PMID: 32037829 DOI: 10.1021/acs.jmedchem.9b01526
Abstract

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.

Figures
Products