Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

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

Covalent inhibitors that target lysine side chains

Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain

Gizem Akçay, Matthew A Belmonte, Brian Aquila, Claudio Chuaqui, Alexander W Hird, Michelle L Lamb, Philip B Rawlins, Nancy Su, Sharon Tentarelli, Neil P Grimster & Qibin Su

Nature Chemical Biology (2016) doi:10.1038/nchembio.2174

Cysteinome: The first comprehensive database for proteins with targetable cysteine and their covalent inhibitors

• Sijin Wu^a, b, 
• Huizhe Luo (Howard)^a, 
• Haina Wang^a, 
• Weijie Zhao^b, 
• Qiwan Hu^a, 
• Yongliang Yang^a, , 

• ^a Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, 116023, PR China
• ^b School of Pharmacology, Dalian University of Technology, Dalian, 116023, PR China

doi: 10.1016/j.bbrc.2016.08.109

http://www.cysteinome.org/