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ACS Chem Biol. 2017 Oct 20;12(10):2491-2497. doi: 10.1021/acschembio.7b00707. Epub 2017 Sep 1.

Synthetic Lethality Triggered by Combining Olaparib with BRCA2-Rad51 Disruptors.

Author information

1
CompuNet, Istituto Italiano di Tecnologia , via Morego 30, I-16163 Genova, Italy.
2
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna , Via S. Giacomo 14, I-40126 Bologna, Italy.
3
Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.
4
TES Pharma S.r.l. , Via Palmiro Togliatti 22bis, I-06073 Loc. Terrioli, Corciano, Perugia, Italy.
5
Department of Experimental Oncology at the European Institute of Oncology, IFOM-IEO Campus , Via Adamello 16, I-20100 Milan, Italy.
6
Department of Biosciences, University of Milan , Via Celoria 26, I-20100 Milan, Italy.

Abstract

In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced synthetic lethality, which was triggered by combining two different small organic molecules. When administered with a BRCA2-Rad51 disruptor in nonmutant cells, Olaparib showed anticancer activity comparable to that shown when administered alone in BRCA2-defective cells. This strategy could represent an innovative approach to anticancer drug discovery and could be extended to other synthetic lethality pathways.

PMID:
28841282
DOI:
10.1021/acschembio.7b00707
[Indexed for MEDLINE]

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