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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

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Molecular Glue Degraders of the RNA Binding Protein HuR to Treat BRAF-Mutant Colorectal Cancer

Project description: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 suppression of BRAF mutant CRC tumors 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 refractory BRAF-mutant CRC patients.

2025-12-21 | PXD072281 |

Molecular Glue Degraders of the HuR RNA Binding Protein to Treat BRAF-Mutant Colorectal Cancer

Project description:Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of HuR

2025-07-29 | PXD066736 |

A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

Project description:Cereblon (CRBN) is a ubiquitin ligase widely harnessed for targeted protein degradation. We report the discovery of a molecular glue that drives CRBN homo-dimerization and subsequent fast, potent, and selective CRBN degradation by the ubiquitin proteasome system. The structure of the complex reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a protein degron in trans.

2025-09-08 | PXD065335 | Pride

A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

2025-09-08 | PXD060544 | Pride

A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

2025-09-08 | PXD060261 | Pride

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

Project description:Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term “template-assisted covalent modification”. We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2 revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for BD2 selectivity. Supporting a general applicability, we find that a subset of compounds leads to a drug-induced GAK-BRD4 interaction stabilized by covalent modification of GAK. Together our work establishes “template-assisted covalent modification” as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.

2024-08-09 | PXD047137 | Pride

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

2024-08-09 | PXD047138 | Pride

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

2024-08-09 | PXD047141 | Pride

Rational and scalable strategies to identify small “molecular glue” degraders

Project description:Rational and scalable strategies to identify small “molecular glue” degraders

| PRJNA596945 | ENA

Overcoming Drug Resistance in Chronic Myeloid Leukemia: Rational Development of Druggable Molecular Glue Degraders

Project description:Overcoming drug resistance remains a major challenge in targeted therapy. Molecular glue degraders offer a promising solution, but their discovery has been largely serendipitous, limiting systematic development. In this study, we report a rational strategy to convert kinase inhibitors into molecular glue degraders that overcome Bcr-AblT315I-mediated resistance in chronic myeloid leukemia (CML). By engineering the solvent-exposed region of GZD824, we generated a covalent degrader that recruits the previously unexploited E3 ligase UBR4 through covalent engagement of C4512. Structural optimization, which replaced the covalent warhead with a minimal ethyl group, yielded compound 4147. This compound achieved potent Bcr-AblT315I degradation (DC₅₀ = 16.18 nM, Dmax = 91.1%), displayed favorable pharmacokinetics (t1/2 = 4.36 h, F = 69.78%), and demonstrated strong in vivo efficacy (67.8% TGI at 20 mg/kg) with minimal toxicity (≤3% body weight loss), markedly outperforming olverembatinib (26.2% TGI). These findings establish 4147 as a clinically tractable molecular glue degrader to overcome T315I-mediated resistance in CML. More broadly, our design strategy can be applied to other marketed kinase inhibitors, such as imatinib (Gleevec) and ponatinib (Iclusig), through minimal structural modifications that preserve drug-like properties. Beyond its therapeutic implications, this work validates UBR4 as a previously unexploited E3 ligase for targeted protein degradation, thereby expanding the ligase repertoire and providing a general framework for the rational development of druggable molecular glue degraders.

2026-03-26 | PXD068712 |

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