Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer

作者：Xiaocui Lu, Xiuyun Wang, Zheng Yang, Xusheng Wang, Lin Wang, Chunhui Xu, I‐Chung Lo, 耿辰璐, Lin Wang, Yisheng Pu, Keyu Zhang, Ziqiang Zhu, Lanxin Ye, Jiayuan Huang, Xiaofan Wei, Fang Bai, Yanan Zhu, Xiaobing Qian, Hao Dou, Hexiu Su, Yong Cang · 发表于：Nature · 年份：2026 · DOI：10.1038/s41586-026-10613-5 · 被引用次数：5 · 研究领域：RNA Research and Splicing、Protein Degradation and Inhibitors、Cancer-related Molecular Pathways

BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse1–3. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by the cryo-electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF-mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF-mutant CRC. Molecular glue degraders of the RNA-binding protein HuR have therapeutic potential for BRAF-mutant cancers.