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

Lavinia Carabet,Nada Lallous,Artem Cherkasov,Joseph Lee,Eric Leblanc,Helene Morin,Paul Rennie,Fariba Ghaidi

doi:10.3390/molecules24040763

Lavinia Carabet, Nada Lallous + Show 6 more

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https://doi.org/10.3390/molecules24040763

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Journal: Molecules (Basel, Switzerland)	Publication Date: Feb 20, 2019
Citations: 31	License type: CC BY 4.0

Affiliation: University of British Columbia

Abstract

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.

Highlights

HnRNP A1 is a multifunctional RNA-binding protein that regulates alternative pre-mRNA splicing, transcription, nucleocytoplasmic shuttling, miRNA processing, and telomere elongation maintenance, as well as translation of cellular transcripts both in physiological and pathological conditions [1,2]
Despite the initial efficacy of androgen deprivation therapy, tumors recur resulting in castration-resistant prostate cancer (CRPC) which often remains dependent on androgen receptor (AR) activity [14]
We report compound VPC-80051, a novel hnRNP A1 small molecule inhibitor targeting the hnRNP A1 RNA-binding domain (RBD), the first to be identified using a computer-aided drug discovery approach

Summary

Introduction

HnRNP A1 is a multifunctional RNA-binding protein that regulates alternative pre-mRNA splicing, transcription, nucleocytoplasmic shuttling, miRNA processing, and telomere elongation maintenance, as well as translation of cellular transcripts both in physiological and pathological conditions [1,2]. Overexpression of hnRNP A1 in various cancer types, including prostate [3,4], lung [5], stomach [6], and breast [7] cancers, Burkitt lymphoma [8], multiple myeloma [9], leukemia [10] and neuroblastoma [11], has been associated with tumorigenesis, cancer progression and drug resistance. In prostate cancer (PCa), the second leading cause of cancer-related death in men, alternative splicing (AS) plays a prominent role as it represents a mechanism of resistance to therapy [3]. Despite the initial efficacy of androgen deprivation therapy, tumors recur resulting in castration-resistant prostate cancer (CRPC) which often remains dependent on AR activity [14]

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