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.

中文翻译：

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在去势抵抗性前列腺癌中靶向 hnRNP A1 RNA 剪接活性的小分子的计算机辅助发现

异质核核糖核蛋白 A1 (hnRNP A1) 是一种多功能的 RNA 结合蛋白，在癌症的替代前 mRNA 剪接调节中发挥关键作用。新出现的数据表明 hnRNP A1 作为剪接调节回路的核心参与者，涉及其由 c-Myc 癌蛋白的直接转录控制以及雄激素受体的组成型活性配体非依赖性选择性剪接变体 AR-V7 的产生，AR-V7 促进去势。耐药性前列腺癌（CRPC）。由于迫切需要有效的 CRPC 药物，因此靶向 hnRNP A1 可以起到防止 AR-V7 生成和减少 c-Myc 转录输出的双重目的。在此处，我们报告了化合物 VPC-80051 作为迄今为止使用计算机辅助药物发现方法发现的第一个 hnRNP A1 剪接活性的小分子抑制剂。该抑制剂旨在靶向 hnRNP A1 的 RNA 结合域 (RBD)。进一步的实验评估表明，VPC-80051 直接与 hnRNP A1 RBD 相互作用并降低 22Rv1 CRPC 细胞系中的 AR-V7 信使水平。这项研究为未来基于结构开发更有效和选择性的 hnRNP A1-RNA 相互作用小分子抑制剂奠定了基础，旨在改变癌症特异性选择性剪接异构体的产生。进一步的实验评估表明，VPC-80051 直接与 hnRNP A1 RBD 相互作用并降低 22Rv1 CRPC 细胞系中的 AR-V7 信使水平。这项研究为未来基于结构开发更有效和选择性的 hnRNP A1-RNA 相互作用小分子抑制剂奠定了基础，旨在改变癌症特异性选择性剪接亚型的产生。进一步的实验评估表明，VPC-80051 直接与 hnRNP A1 RBD 相互作用并降低 22Rv1 CRPC 细胞系中的 AR-V7 信使水平。这项研究为未来基于结构开发更有效和选择性的 hnRNP A1-RNA 相互作用小分子抑制剂奠定了基础，旨在改变癌症特异性选择性剪接亚型的产生。