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

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 an...

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Autores principales:	Z. Ping Lin, Nour N. Al Zouabi, Mark L. Xu, Nicole E. Bowen, Terence L. Wu, Ethan S. Lavi, Pamela H. Huang, Yong-Lian Zhu, Baek Kim, Elena S. Ratner
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7c21bcf75bea4e2ebab41ede567eddbb
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spelling	oai:doaj.org-article:7c21bcf75bea4e2ebab41ede567eddbb2021-12-02T18:03:07ZIn silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer10.1038/s41598-021-87325-52045-2322https://doaj.org/article/7c21bcf75bea4e2ebab41ede567eddbb2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87325-5https://doaj.org/toc/2045-2322Abstract 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.Z. Ping LinNour N. Al ZouabiMark L. XuNicole E. BowenTerence L. WuEthan S. LaviPamela H. HuangYong-Lian ZhuBaek KimElena S. RatnerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-21 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Z. Ping Lin Nour N. Al Zouabi Mark L. Xu Nicole E. Bowen Terence L. Wu Ethan S. Lavi Pamela H. Huang Yong-Lian Zhu Baek Kim Elena S. Ratner In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
description	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.
format	article
author	Z. Ping Lin Nour N. Al Zouabi Mark L. Xu Nicole E. Bowen Terence L. Wu Ethan S. Lavi Pamela H. Huang Yong-Lian Zhu Baek Kim Elena S. Ratner
author_facet	Z. Ping Lin Nour N. Al Zouabi Mark L. Xu Nicole E. Bowen Terence L. Wu Ethan S. Lavi Pamela H. Huang Yong-Lian Zhu Baek Kim Elena S. Ratner
author_sort	Z. Ping Lin
title	In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
title_short	In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
title_full	In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
title_fullStr	In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
title_full_unstemmed	In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
title_sort	in silico screening identifies a novel small molecule inhibitor that counteracts parp inhibitor resistance in ovarian cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7c21bcf75bea4e2ebab41ede567eddbb
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In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer

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