Abstract 6779: Molecular glue degraders of the RNA binding protein HuR to treat BRAF-mutant colorectal cancer

Abstract BRAF gain-of-function mutations, particularly BRAF(V600E), occur in approximately 10% of colorectal cancer (CRC) patients and are associated with poor prognosis and limited therapeutic options. While combined BRAF and EGFR inhibition is a standard of care, its efficacy is transient, often leading to rapid resistance and relapse. HuR is a key driver of tumor growth, invasion, and therapy resistance but was thought to be “undruggable” in the past. Here we identify novel molecular glue degraders. dHuR, as a representative, exhibited strong CRBN binding affinity and HuR degradation potency by recruiting the CRL4-CRBN ubiquitin ligase to target the RNA-binding protein HuR for degradation. Cryo-EM structural analysis revealed that dHuR created a unique benzofuran-tethered interface on CRBN, engaging a β-hairpin G-loop degron on HuR and recruiting it as a neo-substrate. Functionally, degradation of HuR by dHuR induced skipping of exon 18 in the BRAF transcript, leading to reduction in BRAF protein levels. This mechanism resulted in more effective suppression of BRAF-mutant CRC tumor growth in vitro and in vivo, including in models resistant to BRAF inhibitors. In vitro studies showed dHuR potently reduced viability in all 6 BRAF-mutant lines, while BRAF-WT cell lines remained unaffected. Mice bearing Colo205 tumors were treated with dHuR via oral gavage for 28 days. The treatment resulted in dose-dependent tumor growth inhibition. No significant changes in body weight or adverse clinical observations were reported. Furthermore, a comprehensive kinome-wide CRISPR screen identified EGFR and MEK inactivation as potent enhancers of dHuR cytotoxicity, establishing a strong rationale for combination therapy in refractory disease. Based on this compelling preclinical profile, we have advanced a clinical candidate, DEG6498. We are pleased to report the successful clearance of Investigational New Drug (IND) applications from both the U.S. FDA (IND 174949) and China's NMPA (CXHL2500454). A Phase I clinical trial has been initiated to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of DEG6498 in patients with advanced solid tumors, including BRAF-mutant CRC as an expansion cohort. This trial marks a significant milestone as the first-in-human study of a HuR-targeted molecular glue degrader, offering a novel therapeutic strategy with a distinct mechanism of action to overcome the limitations of current targeted therapies for this aggressive cancer subset. Citation Format: Zheng Yang, Xiaocui Lu, Xiuyun Wang, Xusheng Wang, Lin Wang, Chunhui Xu, Chenlu Geng, Lin Wang, Yisheng Pu, Zhiqiang Zhu, Lanxin Ye, Jiayuan Huang, Xiaofan Wei, Fang Bai, Yanan Zhu, Xiaobing Qian, Hao Dou, Hexiu Su, Yong Cang. Molecular glue degraders of the RNA binding protein HuR to treat BRAF-mutant colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6779.