Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13

Yao Liu, Mingfeng Hao, Alan Leggett, Yang Gao, Scott B Ficarro, Jianwei Che, Zhixiang He, Calla Olson, Jarrod A. Marto, Nicholas Kwiatkowski, Tinghu Zhang, and Nathanael S Gray

J. Med. Chem. 2020
https://doi.org/10.1021/acs.jmedchem.9b01929

Genetic depletion of cyclin-dependent kinase 12 (CDK12) or selective inhibition of an analog-sensitive CDK12 reduces DNA damage repair gene expression, but selective inhibition of endogenous CDK12 is difficult. Here, we report the development of MFH290, a novel cysteine (Cys)-directed covalent inhibitor of CDK12/13. MFH290 forms a covalent bond with Cys-1039 of CDK12, exhibits excellent kinome selectivity, inhibits the phosphorylation of serine-2 in the C-terminal domain (CTD) of RNA-polymerase II (Pol II) and reduces the expression of key DNA damage repair genes. Importantly, these effects were demonstrated to be CDK12-dependent as mutation of Cys-1039 rendered the kinase refractory to MFH290 and restored Pol II CTD phosphorylation and DNA damage repair gene expression. Consistent with its effect on DNA damage repair gene expression, MFH290 augments the anti-proliferative effect of the PARP inhibitor, Olaparib.