Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer
7 affiliations
- 1School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China
- 2Degron Therapeutics Co., Ltd, Shanghai, China
- 3Institute for Advanced Study in Physics and ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, China
- 4Degron Therapeutics Co., Ltd, Shanghai, China. [email protected]
- 5Degron Therapeutics Co., Ltd, Shanghai, China. [email protected]
- 6Degron Therapeutics Co., Ltd, Shanghai, China. [email protected]
- 7School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China. [email protected]
Abstract
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.
Related
- Acquired epithelial Wnt7b secretion establishes autocrine WNT dependency in BRAF mutant colorectal cancer
- circSCAF11 Attenuates TGF-β/SMAD2/3 Signaling to Suppress Colorectal Cancer Progression.
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders
- SF3b inhibitors suppress proliferation of nonsmall cell lung cancer cells irrespective of EGFR mutation status
- NEIL2 regulates RNA polymerase II dynamics to suppress transcription replication conflicts in pancreatic cancer
BibTeX
@article{lu2026molecular,
title = {{Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer}},
author = {Xiaocui Lu and Xiuyun Wang and Zheng Yang and Xusheng Wang and Lin Wang and Chunhui Xu and I‐Chung Lo and Chenlu Geng and Lin Wang and Yisheng Pu and Keyu Zhang and Ziqiang Zhu and Lanxin Ye and Jiayuan Huang and Xiaofan Wei and Fang Bai and Yanan Zhu and Xiaobing Qian and Hao Dou and Hexiu Su and Yong Cang},
journal = {Nature},
year = {2026},
month = jun,
doi = {10.1038/s41586-026-10613-5},
url = {https://doi.org/10.1038/s41586-026-10613-5},
note = {CC BY},
}
RIS
TY - JOUR
TI - Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer
AU - Xiaocui Lu
AU - Xiuyun Wang
AU - Zheng Yang
AU - Xusheng Wang
AU - Lin Wang
AU - Chunhui Xu
AU - I‐Chung Lo
AU - Chenlu Geng
AU - Lin Wang
AU - Yisheng Pu
AU - Keyu Zhang
AU - Ziqiang Zhu
AU - Lanxin Ye
AU - Jiayuan Huang
AU - Xiaofan Wei
AU - Fang Bai
AU - Yanan Zhu
AU - Xiaobing Qian
AU - Hao Dou
AU - Hexiu Su
AU - Yong Cang
PY - 2026
DA - 2026/06/10
JO - Nature
DO - 10.1038/s41586-026-10613-5
UR - https://doi.org/10.1038/s41586-026-10613-5
AB - 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.
SN - 0028-0836
SN - 1476-4687
ER -