In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer

• Type of Material: Article
• Authors: Z. Ping Lin, Yale University; Nour N. Al Zouabi, Yale University; Mark L. Xu, Yale University; Nicole E. Bowen, Emory University; Terence L. Wu, Yale University; Ethan S. Lavi, Yale University; Pamela H. Huang, Yale University; Yong-Lian Zhu, Yale University; Baek Kim, Emory University; Elena S. Ratner, Yale University
• Language: English
• Date: 2021-04-13
• Publisher: Nature Portfolio
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-021-87325-5
• Title of Journal or Parent Work: Scientific Reports
• Volume: 11
• Issue: 1
• Start Page: 8042
• End Page: 8042
• Grant/Funding Information: This work was supported by the Discovery to Cure Program at Yale University (Z.P.L and E.S.R) and by National Institutes of Health Grants AI136581 and AI150451 (to B. K.).; Z. Ping Lin and Elena S. Ratner are Discovery to Cure Fellows.
• Keywords: 3-AP; Radiochemotherapy; Mechanism; Science & Technology; Rubenocleotide; Multidisciplinary Sciences; Mutations; Polymerase; Homologous recombination repair; Cisplatin; Science & Technology - Other Topics; Cell growth
• Research Categories: Health Sciences, Oncology; Biology, Cell; Health Sciences, Human Development; Health Sciences, Pharmacology

Abstract

Poly ADP-ribose polymerase (PARP) inhibitors are promising targeted therapy for epithelial ovarian cancer (EOC) with BRCA mutations or defective homologous recombination (HR) repair. However, reversion of BRCA mutation and restoration of HR repair in EOC lead to PARP inhibitor resistance and reduced clinical efficacy of PARP inhibitors. We have previously shown that triapine, a small molecule inhibitor of ribonucleotide reductase (RNR), impaired HR repair and sensitized HR repair-proficient EOC to PARP inhibitors. In this study, we performed in silico screening of small molecule libraries to identify novel compounds that bind to the triapine-binding pocket on the R2 subunit of RNR and inhibit RNR in EOC cells. Following experimental validation of selected top-ranking in silico hits for inhibition of dNTP and DNA synthesis, we identified, DB4, a putative RNR pocket-binding inhibitor markedly abrogated HR repair and sensitized BRCA-wild-type EOC cells to the PARP inhibitor olaparib. Furthermore, we demonstrated that the combination of DB4 and olaparib deterred the progression of BRCA-wild type EOC xenografts and significantly prolonged the survival time of tumor-bearing mice. Herein we report the discovery of a putative small molecule inhibitor of RNR and HR repair for combination with PARP inhibitors to treat PARP inhibitor-resistant and HR repair-proficient EOC.