Compound F779-0434 Causes Synthetic Lethality in BRCA2-deficient Cancer Cells by Disrupting RAD52-ssDNA Association

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 May 11

PMID 35539677

Authors

Jian Li

Qianye Yang

Yang Zhang

Kejia Huang

Rong Sun

Qi Zhao

Affiliations

Soon will be listed here.

Abstract

Maintenance of genomic integrity is essential for the survival of all organisms. Homologous recombination (HR) is the major pathway for high-fidelity repair of DNA double-stranded breaks (DSBs). In addition to the classic BRCA-RAD51 pathway, another secondary HR sub-pathway dependent on RAD52 has been suggested to be functioning in mammalian cells. Importantly, RAD52 has been shown to be synthetically lethal to BRCA1/2-deficient cells, rendering RAD52 to be a desirable target in cancer therapy. In the current study, we performed a structure-based virtual screening of 47 737 drug-like compounds to identify RAD52-specific inhibitors. The top ranked virtual screening hits were further characterized using molecular dynamics simulation and biochemical and cell-based assays. We found that one compound, namely, F779-0434 specifically suppressed the growth of BRCA2-deficient cells and disrupted RAD52-ssDNA interaction . This RAD52-specific inhibitor identified in the current study is a promising compound for targeted cancer therapy, and it can also be used as a probe to study the mechanisms of DNA repair in human cells.

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References

Feng Z, Scott S, Bussen W, Sharma G, Guo G, Pandita T . Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc Natl Acad Sci U S A. 2010; 108(2):686-91. PMC: 3021033. DOI: 10.1073/pnas.1010959107. View

Farmer H, McCabe N, Lord C, Tutt A, Johnson D, Richardson T . Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434(7035):917-21. DOI: 10.1038/nature03445. View

Antoniou A, Casadei S, Heikkinen T, Barrowdale D, Pylkas K, Roberts J . Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014; 371(6):497-506. PMC: 4157599. DOI: 10.1056/NEJMoa1400382. View

Lloyd J, Forget A, Knight K . Correlation of biochemical properties with the oligomeric state of human rad52 protein. J Biol Chem. 2002; 277(48):46172-8. DOI: 10.1074/jbc.M207262200. View

Lok B, Carley A, Tchang B, Powell S . RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination. Oncogene. 2012; 32(30):3552-8. PMC: 5730454. DOI: 10.1038/onc.2012.391. View

Cramer-Morales K, Nieborowska-Skorska M, Scheibner K, Padget M, Irvine D, Sliwinski T . Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. Blood. 2013; 122(7):1293-304. PMC: 3744994. DOI: 10.1182/blood-2013-05-501072. View

Sullivan K, Cramer-Morales K, McElroy D, Ostrov D, Haas K, Childers W . Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection. PLoS One. 2016; 11(1):e0147230. PMC: 4718542. DOI: 10.1371/journal.pone.0147230. View

Wallace A, Laskowski R, Thornton J . LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng. 1995; 8(2):127-34. DOI: 10.1093/protein/8.2.127. View

King M, Marks J, Mandell J . Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003; 302(5645):643-6. DOI: 10.1126/science.1088759. View

10.

Kapetanovic I . Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach. Chem Biol Interact. 2007; 171(2):165-76. PMC: 2253724. DOI: 10.1016/j.cbi.2006.12.006. View

11.

Rouleau M, Patel A, Hendzel M, Kaufmann S, Poirier G . PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010; 10(4):293-301. PMC: 2910902. DOI: 10.1038/nrc2812. View

12.

van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark A, Berendsen H . GROMACS: fast, flexible, and free. J Comput Chem. 2005; 26(16):1701-18. DOI: 10.1002/jcc.20291. View

13.

Moynahan M, Jasin M . Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol. 2010; 11(3):196-207. PMC: 3261768. DOI: 10.1038/nrm2851. View

14.

Lord C, Ashworth A . The DNA damage response and cancer therapy. Nature. 2012; 481(7381):287-94. DOI: 10.1038/nature10760. View

15.

Iyama T, Wilson 3rd D . DNA repair mechanisms in dividing and non-dividing cells. DNA Repair (Amst). 2013; 12(8):620-36. PMC: 3720834. DOI: 10.1016/j.dnarep.2013.04.015. View

16.

Sung P, Klein H . Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol. 2006; 7(10):739-50. DOI: 10.1038/nrm2008. View

17.

Lok B, Powell S . Molecular pathways: understanding the role of Rad52 in homologous recombination for therapeutic advancement. Clin Cancer Res. 2012; 18(23):6400-6. PMC: 3513650. DOI: 10.1158/1078-0432.CCR-11-3150. View

18.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

19.

Ashworth A . A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008; 26(22):3785-90. DOI: 10.1200/JCO.2008.16.0812. View

20.

Pronk S, Pall S, Schulz R, Larsson P, Bjelkmar P, Apostolov R . GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013; 29(7):845-54. PMC: 3605599. DOI: 10.1093/bioinformatics/btt055. View