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Discovery and resistance mechanism of a selective CDK12 degrader.

Nature chemical biology (2021-03-24)
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
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-RNA polymerase II subunit B1 (phospho CTD Ser-2), clone 3E10 (rat monoclonal)., culture supernatant, clone 3E10, from rat
Sigma-Aldrich
Anti-phospho-RNAPII Antibody (Thr4), clone 1G7, clone 1G7, from rat
Sigma-Aldrich
Anti-RNA polymerase II subunit B1 (phospho-CTD Ser-5) Antibody, clone 3E8, culture supernatant, clone 3E8, from rat
Sigma-Aldrich
Anti-RNA polymerase II subunit B1 (phospho-CTD Ser-7) Antibody, clone 4E12, culture supernatant, clone 4E12, from rat