2. Academic Validation
  3. Identification of a RAD52 Inhibitor Inducing Synthetic Lethality in BRCA2-Deficient Cancer Cells

Identification of a RAD52 Inhibitor Inducing Synthetic Lethality in BRCA2-Deficient Cancer Cells

  • Front Pharmacol. 2021 Apr 29:12:637825. doi: 10.3389/fphar.2021.637825.
Qianye Yang 1 2,  Yu Li 3,  Rong Sun 4,  Jian Li 1 2 5
Affiliations

Affiliations

  • 1 Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, China.
  • 2 Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China.
  • 3 West China School of Pharmacy, Sichuan University, Chengdu, China.
  • 4 Basic medical research center, School of medicine, Nantong University, Nantong, China.
  • 5 School of Medicine, Chengdu University, Chengdu, China.
PMID: 33995041 DOI: 10.3389/fphar.2021.637825
Abstract

The breast Cancer susceptibility gene 1/2 (BRCA1/2) is frequently mutated in many malignant tumors, such as breast Cancer and ovarian Cancer. Studies have demonstrated that inhibition of RAD52 gene function in BRCA2-deficient Cancer causes synthetic lethality, suggesting a potential application of RAD52 in cancer-targeted therapy. In this study, we have performed a virtual screening by targeting the self-association domain (residues 85-159) of RAD52 with a library of 66,608 compounds and found one compound, C791-0064, that specifically inhibited the proliferation of BRCA2-deficient Cancer cells. Our biochemical and cell-based experimental data suggested that C791-0064 specifically bound to RAD52 and disrupted the single-strand annealing activity of RAD52. Taken together, C791-0064 is a promising leading compound worthy of further exploitation in the context of BRCA-deficient targeted Cancer therapy.

Keywords

BRCA2 deficiency; Rad52; molecular dynamics; self-association; synthetic lethality.

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