Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells

Marinella Roberti, Fabrizio Schipani, Greta Bagnolini, Domenico Milano, Elisa Giacomini, Federico Falchi, Andrea Balboni, Marcella Manerba, Fulvia Farabegoli, Francesca De Franco, Janet Robertson, Saverio Minucci, Isabella Pallavicini, Giuseppina Di Stefano, Stefania Girotto, Roberto Pellicciari, Andrea Cavalli

Research output: Contribution to journalArticle

Abstract

Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.

Original languageEnglish
Pages (from-to)80-92
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume165
DOIs
Publication statusPublished - Mar 1 2019

Keywords

  • Anticancer drugs
  • Homologous recombination
  • PARP inhibitors
  • Protein-protein small molecule inhibitors
  • Synthetic lethality

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Roberti, M., Schipani, F., Bagnolini, G., Milano, D., Giacomini, E., Falchi, F., Balboni, A., Manerba, M., Farabegoli, F., De Franco, F., Robertson, J., Minucci, S., Pallavicini, I., Di Stefano, G., Girotto, S., Pellicciari, R., & Cavalli, A. (2019). Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells. European Journal of Medicinal Chemistry, 165, 80-92. https://doi.org/10.1016/j.ejmech.2019.01.008