2. Academic Validation
  3. An 19F NMR fragment-based approach for the discovery and development of BRCA2-RAD51 inhibitors to pursuit synthetic lethality in combination with PARP inhibition in pancreatic cancer

An 19F NMR fragment-based approach for the discovery and development of BRCA2-RAD51 inhibitors to pursuit synthetic lethality in combination with PARP inhibition in pancreatic cancer

  • Eur J Med Chem. 2024 Feb 5:265:116114. doi: 10.1016/j.ejmech.2023.116114.
Samuel H Myers 1,  Laura Poppi 2,  Francesco Rinaldi 3,  Marina Veronesi 4,  Andrea Ciamarone 1,  Viola Previtali 1,  Greta Bagnolini 2,  Fabrizio Schipani 1,  Jose Antonio Ortega Martínez 1,  Stefania Girotto 5,  Giuseppina Di Stefano 6,  Fulvia Farabegoli 2,  Naomi Walsh 7,  Francesca De Franco 8,  Marinella Roberti 9,  Andrea Cavalli 10
Affiliations

Affiliations

  • 1 Computational and Chemical Biology, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
  • 2 Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy.
  • 3 Computational and Chemical Biology, Istituto Italiano di Tecnologia, 16163, Genoa, Italy; Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy.
  • 4 Structural Biophysics Facility, Istituto Italiano di Tecnologia, 16163, Genoa, Italy; D3 PharmaChemistry, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
  • 5 Computational and Chemical Biology, Istituto Italiano di Tecnologia, 16163, Genoa, Italy; Structural Biophysics Facility, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
  • 6 Department of Surgical and Medical Sciences, University of Bologna, 40126, Bologna, Italy.
  • 7 School of Biotechnology, Dublin City University, D09 NR58, Dublin, Ireland.
  • 8 TES Pharma S.r.l., I-06073, Corciano, Perugia, Italy.
  • 9 Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy. Electronic address: marinella.roberti@unibo.it.
  • 10 Computational and Chemical Biology, Istituto Italiano di Tecnologia, 16163, Genoa, Italy; Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland.
PMID: 38194775 DOI: 10.1016/j.ejmech.2023.116114
Abstract

The BRCA2-RAD51 interaction remains an intriguing target for Cancer drug discovery due to its vital role in DNA damage repair mechanisms, which Cancer cells become particularly reliant on. Moreover, RAD51 has many synthetically lethal partners, including PARP1-2, which can be exploited to induce synthetic lethality in Cancer. In this study, we established a 19F-NMR-fragment based approach to identify RAD51 binders, leading to two initial hits. A subsequent SAR program identified 46 as a low micromolar inhibitor of the BRCA2-RAD51 interaction. 46 was tested in different pancreatic Cancer cell lines, to evaluate its ability to inhibit the homologous recombination DNA repair pathway, mediated by BRCA2-RAD51 and trigger synthetic lethality in combination with the PARP Inhibitor talazoparib, through the induction of Apoptosis. Moreover, we further analyzed the 46/talazoparib combination in 3D pancreatic Cancer Models. Overall, 46 showed its potential as a tool to evaluate the RAD51/PARP1-2 synthetic lethality mechanism, along with providing a prospect for further inhibitors development.

Keywords

BRCA2-RAD51; NMR fragment-based screening; PARP inhibition; Pancreatic cancer; Synthetic lethality.

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