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.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter and @firstname.lastname@example.org on Mastodon
Tuesday, September 20, 2016
Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors
Covalent drug discovery using sulfur(VI) fluoride exchange warheads
Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 https://doi.org/10.1080/17460441.2023.2218642 Covalent drug discovery has ...
Zhao, Z.; Bourne, P. E. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-nlb0m Kinase-targeted drug discovery for cancer therapy ha...
Wang, S.; Hadisurya, M.; Tao, W. A.; Dykhuizen, E.; Krusemark, C. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-tvgn1 Targeted co...
Jian Ding, Guo Li, Hejun Liu, Lulu Liu, Ying Lin, Jingyan Gao, Guoqiang Zhou, Lingling Shen, Mengxi Zhao, Yanyan Yu, Weihui Guo, Ulrich Homm...