Evidence map›Paper›PMID 42492625›Full record

ArticleBioorganic & medicinal chemistry letters2026

An optimized RNF126-targeting covalent handle for molecular glue degraders.

Aman Modi, Ethan S Toriki, Christian E Stieger, Emily A Lau, Claire Song, Alyssa Chew, Amy Tsao, Kaila Nishikawa, Jeffrey McKenna, Daniel K Nomura

Abstract read
PubMed Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry letters, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Covalent Reprogramming of Kinase Binders to Modulate Protein Abundance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors.

Aman ModiDepartments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA.
Ethan S TorikiDepartments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA; Novartis BioMedical Research, Cambridge, MA, USA.
Christian E StiegerDepartments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA.
Emily A LauDepartments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA.
Claire SongDepartments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA.
Alyssa ChewDepartments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA.
Amy TsaoDepartments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA.
Kaila NishikawaDepartments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA.
Jeffrey McKennaNovartis-Berkeley Translational Chemical Biology Institute, USA; Novartis BioMedical Research, Cambridge, MA, USA.
Daniel K NomuraDepartments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA. Electronic address: dnomura@berkeley.edu.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Molecular glue degraders represent a powerful modality for targeting proteins that are refractory to traditional inhibition. However, rational design principles for molecular glue degraders remain poorly defined. Previously, we reported a chemistry-centric strategy to identify covalent degradative handles that, when appended to established ligands, convert non-degradative inhibitors into molecular glue degraders by engaging permissive E3 ligases. This effort identified a fumarate-based electrophilic handle that covalently modified the E3 ligase RNF126, enabling degradation of multiple protein targets when transplanted across diverse ligands. Despite its conceptual impact, the high intrinsic reactivity and cytotoxicity of the fumarate handle limited its translational utility. Here, we report the development of an optimized and metabolically stabilized RNF126-targeting covalent handle incorporating a trans-cyclobutane linker that exhibits reduced glutathione reactivity and diminished cytotoxicity while retaining robust degradative activity. When appended to the BET bromodomain inhibitor JQ1, this optimized handle yielded a potent and selective BRD4 degrader whose activity was dependent on RNF126. Importantly, transplantation of this handle onto a previously non-inhibitory ligand targeting the androgen receptor (AR) and its truncation variant, AR-V7, enabled selective degradation of both AR and AR-V7 in androgen-independent prostate cancer cells, thereby robustly inhibiting AR transcriptional activity beyond the established AR antagonist enzalutamide. Collectively, these findings demonstrate an optimized RNF126-based covalent handle for the rational development of molecular glue degraders against transcriptional regulators, including undruggable variants such as AR-V7.

Indexed as

Ubiquitin-Protein LigasesBromodomain Containing ProteinsCell Cycle ProteinsHumansMolecular StructureReceptors, AndrogenStructure-Activity RelationshipTranscription FactorsBRD4 protein, humanBromodomain Containing ProteinsCell Cycle ProteinsReceptors, AndrogenTranscription FactorsUbiquitin-Protein LigasesActivity-based protein profilingAndrogen receptorAR-V7BRD4CovalentE3 ligaseRNF126Targeted protein degradation

Identifiers

PMID42492625

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.