Small Molecules Targeting the RNA-Binding Protein HuR Inhibit Tumor Growth in Xenografts

The RNA-binding protein Hu antigen R (HuR) is a post-transcriptional regulator critical in several types of diseases, including cancer, making it a promising therapeutic target. We have identified small-molecule inhibitors of HuR through a screening approach used in combination with fragment analysis. A total of 36 new compounds originating from fragment linking or structural optimization were studied to establish structure–activity relationships in the set. Two top inhibitors, 1c and 7c, were further validated by binding assays and cellular functional assays. Both block HuR function by directly binding to the RNA-binding pocket, inhibit cancer cell growth dependence of HuR, and suppress cancer cell invasion. Intraperitoneal administration of inhibitor 1c inhibits tumor growth as a single agent and shows a synergistic effect in combination with chemotherapy docetaxel in breast cancer xenograft models. Mechanistically, 1c interferes with the HuR–TGFB/THBS1 axis.

RNA结合蛋白Hu抗原R（Hu antigen R）是一类关键的转录后调控因子，在包括癌症在内的多种疾病中发挥核心作用，因此成为极具潜力的治疗靶点。本研究通过整合片段分析的筛选策略，鉴定得到HuR的小分子抑制剂。我们共计研究了36种源自片段连接或结构优化的全新化合物，以明确该系列化合物的构效关系。选取两款最优抑制剂1c与7c，通过结合实验与细胞功能实验完成了进一步验证。二者均可通过直接结合HuR的RNA结合口袋阻断其功能，抑制HuR依赖的癌细胞增殖，并抑制癌细胞侵袭。在乳腺癌异种移植模型中，单药腹腔给药抑制剂1c可单独抑制肿瘤生长，且与化疗药物多西他赛联合使用时展现出协同效应。机制层面，1c可干扰HuR–TGFB/THBS1信号轴。