Open AccessDiscovery and resistance mechanism of a selective CDK12 degrader
Author(s) -
Baishan Jiang,
Yang Gao,
Jianwei Che,
Wenchao Lu,
Ines H. Kaltheuner,
Ruben Dries,
Marian Kalocsay,
Matthew J. Berberich,
Jie Jiang,
Inchul You,
Nicholas Kwiatkowski,
Kristin M. Riching,
Danette L. Daniels,
Peter K. Sorger,
Matthias Geyer,
Tinghu Zhang,
Nathanael S. Gray
Publication year - 2021
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-021-00765-y
Subject(s) - biology , cyclin dependent kinase , dna damage , poly adp ribose polymerase , kinase , microbiology and biotechnology , genetic screen , genetics , gene , cell cycle , mutant , polymerase , dna
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.