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Open AccessArticle

Computer-Aided Discovery of Small Molecules Targeting the RNA Splicing Activity of hnRNP A1 in Castration-Resistant Prostate Cancer

Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada
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Academic Editor: Kok Hwa Lim
Molecules 2019, 24(4), 763; https://doi.org/10.3390/molecules24040763
Received: 19 January 2019 / Revised: 8 February 2019 / Accepted: 16 February 2019 / Published: 20 February 2019
(This article belongs to the Special Issue QSAR and QSPR: Recent Developments and Applications)
The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a versatile RNA-binding protein playing a critical role in alternative pre-mRNA splicing regulation in cancer. Emerging data have implicated hnRNP A1 as a central player in a splicing regulatory circuit involving its direct transcriptional control by c-Myc oncoprotein and the production of the constitutively active ligand-independent alternative splice variant of androgen receptor, AR-V7, which promotes castration-resistant prostate cancer (CRPC). As there is an urgent need for effective CRPC drugs, targeting hnRNP A1 could, therefore, serve a dual purpose of preventing AR-V7 generation as well as reducing c-Myc transcriptional output. Herein, we report compound VPC-80051 as the first small molecule inhibitor of hnRNP A1 splicing activity discovered to date by using a computer-aided drug discovery approach. The inhibitor was developed to target the RNA-binding domain (RBD) of hnRNP A1. Further experimental evaluation demonstrated that VPC-80051 interacts directly with hnRNP A1 RBD and reduces AR-V7 messenger levels in 22Rv1 CRPC cell line. This study lays the groundwork for future structure-based development of more potent and selective small molecule inhibitors of hnRNP A1–RNA interactions aimed at altering the production of cancer-specific alternative splice isoforms. View Full-Text
Keywords: hnRNP A1; alternative splicing; castration-resistant prostate cancer; computer-aided drug discovery; small molecule inhibitors; protein–RNA interactions hnRNP A1; alternative splicing; castration-resistant prostate cancer; computer-aided drug discovery; small molecule inhibitors; protein–RNA interactions
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MDPI and ACS Style

Carabet, L.A.; Leblanc, E.; Lallous, N.; Morin, H.; Ghaidi, F.; Lee, J.; Rennie, P.S.; Cherkasov, A. Computer-Aided Discovery of Small Molecules Targeting the RNA Splicing Activity of hnRNP A1 in Castration-Resistant Prostate Cancer. Molecules 2019, 24, 763.

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