Tinghu Zhang, Nicholas Kwiatkowski, Calla M Olson, Sarah E Dixon-Clarke, Brian J Abraham, Ann K Greifenberg, Scott B Ficarro, Jonathan M Elkins, Yanke Liang, Nancy M Hannett, Theresa Manz, Mingfeng Hao, Bartlomiej Bartkowiak, Arno L Greenleaf, Jarrod A Marto, Matthias Geyer, Alex N Bullock, Richard A Young & Nathanael S Gray
Nature Chemical Biology 12, 787–794 (2016)
Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the
absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy
cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531.
Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside
the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated
RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key
super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically
induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer
subtypes that are particularly dependent on their kinase activities.
doi: 10.1038/nchembio.2166
