Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells
Creators
- Marinella Roberti1
- Fabrizio Schipani2
- Greta Bagnolini3
- Domenico Milano2
- Elisa Giacomini2
- Federico Falchi2
- Andrea Balboni4
- Marcella Manerba5
- Fulvia Farabegoli1
- Francesca De Franco6
- Janet Robertson6
- Saverio Minucci7
- Isabella Pallavicini8
- Giuseppina Di Stefano5
- Stefania Girotto2
- Roberto Pellicciari6
- Andrea Cavalli9
- 1. Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy
- 2. Computational & Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova, Italy
- 3. Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy< Computational & Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova, Italy
- 4. Computational & Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova, Italy; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via S. Giacomo 14, 40126, Bologna, Italy
- 5. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via S. Giacomo 14, 40126, Bologna, Italy
- 6. TES Pharma S.r.l., Via Palmiro Togliatti 22bis, I-06073, Loc. Terrioli, Corciano, Perugia, Italy
- 7. Department of Experimental Oncology at the European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20100, Milan, Italy; Department of Biosciences, University of Milan, Via Celoria 26, 20100, Milan, Italy
- 8. Department of Experimental Oncology at the European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20100, Milan, Italy
- 9. Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy; Computational & Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova, Italy
Description
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
Notes
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