ArticleNature communications2024
Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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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
8 citing papers in PubMed.
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- Molecular glue degraders: Rational design, specificity engineering, and advanced delivery.Acta pharmaceutica Sinica. B · 2026Review
- TPDdb: the comprehensive database of targeted protein degrader.Nucleic acids research · 2026Article
- CDK12 and CDK13 in oncology: from RNA regulation to therapeutic targeting.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Molecular Glues Stabilize Water-Mediated Hydrogen Bonds in Ternary Complexes.Chemphyschem : a European journal of chemical physics and physical chemistry · 2026Article
- Targeted Histone Deacetylase Degradation via Chemical Induced Proximity by Direct Recruitment of the CUL4 Complex Adaptor Protein DDB1.ACS medicinal chemistry letters · 2025Article
- Evaluation of Small-Molecule Binding Site Prediction Methods on Membrane-Embedded Protein Interfaces.Journal of chemical information and modeling · 2025Article
- DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition.EMBO reports · 2025Article
Corrections and comments
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Authors and funding
20 authors.
Funding
Abstract
Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery, albeit with significant challenges. In this study, we propose a dual-site approach, targeting the PPI region and its dynamic surroundings. We conduct molecular dynamics simulations to identify critical sites on the PPI that stabilize the cyclin-dependent kinase 12 - DNA damage-binding protein 1 (CDK12-DDB1) complex, resulting in further cyclin K degradation. This exploration leads to the creation of LL-K12-18, a dual-site molecular glue, which enhances the glue properties to augment degradation kinetics and efficiency. Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues.
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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.