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

Qianye Yang; Yu Li; Rong Sun; Jian Li

doi:10.3389/fphar.2021.637825

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. eCollection 2021.

Authors

Qianye Yang^{1

2}, Yu Li³, Rong Sun⁴, Jian Li^{1

2

5}

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.

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.