Molecular Glue Degraders of HuR to Treat BRAF-Mutant Colorectal Cancer

ABSTRACT: BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all colorectal cancer (CRC) patients, and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as Encorafenib are ineffective due to MAP kinase pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, though 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 tumor growth, invasion, and therapy resistance. dHuR binds 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 Cryo-EM structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppr

ORGANISM(S): Homo Sapiens

SUBMITTER: Yong Cang  

PROVIDER: PXD077365 | iProX | Sun Apr 19 00:00:00 BST 2026

REPOSITORIES: iProX