Discovery and resistance mechanism of a selective CDK12 degrader

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 CDK...

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Published inNature chemical biology Vol. 17; no. 6; pp. 675 - 683
Main Authors Jiang, Baishan, Gao, Yang, Che, Jianwei, Lu, Wenchao, Kaltheuner, Ines H, Dries, Ruben, Kalocsay, Marian, Berberich, Matthew J, Jiang, Jie, You, Inchul, Kwiatkowski, Nicholas, Riching, Kristin M, Daniels, Danette L, Sorger, Peter K, Geyer, Matthias, Zhang, Tinghu, Gray, Nathanael S
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.06.2021
Subjects
Adenosine diphosphate
Adenylation
Animals
Chronic exposure
Cyclin-dependent kinase
Cyclin-dependent kinases
Cyclin-Dependent Kinases - drug effects
Degradation
Deoxyribonucleic acid
DNA
DNA damage
DNA Damage - genetics
Domains
Drug Design
Drug Discovery
Drug Resistance
Genes
Homology
Humans
Kinases
Molting
Mutation
Poly A - metabolism
Poly Adenosine Diphosphate Ribose - metabolism
Poly(ADP-ribose)
Poly(ADP-ribose) polymerase
Protein Kinase Inhibitors - pharmacology
Proteomics
Ribose
Transcription
Tumor cells
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Summary: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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N.S.G. and T.Z. conceived the project; B.J. performed the compound synthesis and structure determination with help from I.Y.; Y.G. and W. L. executed cellular biological experimental research with help from J.J.; K. R and D. D. performed the NanoBRET ternary complex assays. J.C. executed computational modelling, whole exome sequencing analysis and mutational experiments design; R.D. and Y.G. performed genomic data analysis; I.K and M.G. executed CDK12 in vitro kinase assay; M.B. M.K and P.K.S. performed proteomic analysis; T.Z. Y.G. J.C. B.J. and N.S.G co-wrote the paper. All authors edited the manuscript.
Author Contributions
ISSN:1552-4450
1552-4469
DOI:10.1038/s41589-021-00765-y