ArticleeLife2020
Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation.
Article in eLife, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
What it found
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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.
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.
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Who cites it
92 citing papers in PubMed, 195 citations in OpenAlex.
- High-throughput ligand diversification to discover chemical inducers of proximity.Nature chemical biology · 2026Article
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- Cyclin K condensates bridge CDK12 to phosphorylate and drive oncogenic YAP activation in hepatocellular carcinoma.Science advances · 2026Article
- Molecular glue degraders: Rational design, specificity engineering, and advanced delivery.Acta pharmaceutica Sinica. B · 2026Review
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- DNA-Encoded Library (DEL) Selection Identifies a Distinct DDB1 Ligand Binding Site.ACS medicinal chemistry letters · 2026Article
- Induced proximity-based therapeutic modalities.Nature reviews. Drug discovery · 2026Review
- Hydrophobic tagging: A promising paradigm for targeted protein degradation.Cell insight · 2026Review
- Targeting CDK12/13 Drives Mitotic Arrest to Overcome Resistance to KRASG12C Inhibitors.Cancer research · 2026Article
- Clues for glues: from serendipity to nature's blueprints in degrader discovery.Essays in biochemistry · 2025Review
- Orthosteric Molecular Glue Inhibits COP9 Signalosome with Substrate-Dependent Potency.bioRxiv : the preprint server for biology · 2025Article
- Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges.Signal transduction and targeted therapy · 2025Review
- A functional map of CDK-drug interactions at single amino acid resolution.bioRxiv : the preprint server for biology · 2025Article
- Hydrogen-Deuterium Exchange Mass Spectrometry for Molecular Glue Characterization.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- A small-molecule VHL molecular glue degrader for cysteine dioxygenase 1.Nature chemical biology · 2025Article
- Targeting Transcriptional Cyclin-Dependent Kinases in Cancer.Molecular cancer therapeutics · 2025Review
- Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders.Angewandte Chemie (International ed. in English) · 2025Article
- EGFR: New Insights on Its Activation and Mutation in Tumor and Tumor Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review.Journal of Zhejiang University. Science. B · 2025Review
- Unbiased mapping of cereblon neosubstrate landscape by high-throughput proteomics.Nature communications · 2025Article
32 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation.
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Registered trials
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 OpenQuestion graph.