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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Vydané v:	Nature chemical biology Ročník 17; číslo 6; s. 675 - 683
Hlavní autori:	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.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.06.2021 Nature Publishing Group
Predmet:	631/337/572 631/67/1059 631/92/275 631/92/613 Adenosine diphosphate Adenylation Animals Biochemical Engineering Biochemistry Bioorganic Chemistry Cell Biology Chemistry Chemistry and Materials Science Chemistry/Food Science 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
ISSN:	1552-4450, 1552-4469, 1552-4469
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Shrnutí:	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. The discovery of a specific CDK12 bivalent degrader, BSJ-4-116, reveals that chronic exposure of MOLT-4 and Jurkat cells to BSJ-4-116 leads to acquired resistance to the compound via point mutations in the CDK12 kinase domain.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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 1552-4469
DOI:	10.1038/s41589-021-00765-y