Discovery and resistance mechanism of a selective CDK12 degrader
Open accessAbstract
Cyclin-dependent kinase 12 (CDK12) is an emerging therapeutic target due to its role in regulating transcription of DNA-damage response (DDR) genes. However, development of selective small molecules targeting CDK12 has been challenging due to the high degree of homology between kinase domains of CDK12 and other transcriptional CDKs, most notably CDK13. In the present study, we report the rational design and characterization of a CDK12-specific degrader, BSJ-4-116. BSJ-4-116 selectively degraded CDK12 as assessed through quantitative proteomics. Selective degradation of CDK12 resulted in premature cleavage and poly(adenylation) of DDR genes. Moreover, BSJ-4-116 exhibited potent antiproliferative effects, alone and in combination with the poly(ADP-ribose) polymerase inhibitor olaparib, as well as when used as a single agent against cell lines resistant to covalent CDK12 inhibitors. Two point mutations in CDK12 were identified that confer resistance to BSJ-4-116, demonstrating a potential mechanism that tumor cells can use to evade bivalent degrader molecules.
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Mutations can also arise on the neo-substrate, as reported for CDK12-targeting PROTACs.
“While it appears reasonable to conclude that resistance-causing mutations will be enriched in the ligase, mutations can also arise on the neo-substrate, as for instance reported for CDK12-targeting PROTACs47.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [47]
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- Authors
- Jiang, B., Gao, Y., Che, J., Lu, W., Kaltheuner, I. H., Dries, R., Kalocsay, M., Berberich, M. J., Jiang, J., You, I., Kwiatkowski, N., Riching, K. M., Daniels, D. L., Sorger, P. K., Geyer, M., Zhang, T., & Gray, N. S.
- Affiliations
- Harvard University (US)
- University of Bonn (DE)
- Boston University (US)
- Promega (United States) (US)
- Corresponding author
- Zhang, Tinghu
- Gray, Nathanael S.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2021-03-22
- Volume
- 17
- Issue
- 6
- Pages
- 675-683
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC8590456
- OpenAlex
- W3136984727
- Cited by
- 150
- References
- 52
- Citations by year
- 2026: 25 · 2025: 30 · 2024: 30 · 2023: 23 · 2022: 31 · 2021: 10
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (GE 976/9-2)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- CDK12, DNA damage response, CDK13, acquired drug resistance, point mutations, PARP inhibitors, olaparib, antiproliferative activity, MOLT-4 cells, Jurkat cells
- MeSH terms
- Animals, DNA Damage, Drug Resistance, Humans, Poly A, Poly Adenosine Diphosphate Ribose, Drug Design, Cyclin-Dependent Kinases, Proteomics, Protein Kinase Inhibitors, Drug Discovery
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