Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13.,Journal of Medicinal Chemistry

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Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-05 , DOI: 10.1021/acs.jmedchem.9b01929
Yao Liu _{1,

2} , Mingfeng Hao _{1,

2} , Alan L Leggett _{1,

2} , Yang Gao _{1,

2} , Scott B Ficarro _{1,

2,

3} , Jianwei Che _{1,

2} , Zhixiang He _{1,

2} , Calla M Olson _{1,

2} , Jarrod A Marto _{1,

2,

3} , Nicholas P Kwiatkowski _{1,

2} , Tinghu Zhang _{1,

2} , Nathanael S Gray _{1,

2}

Affiliation

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 antiproliferative effect of the PARP inhibitor olaparib.

中文翻译：

MFH290的发现：细胞周期蛋白依赖性激酶12/13的强效高选择性共价抑制剂。

细胞周期蛋白依赖性激酶12（CDK12）的遗传耗竭或类似物敏感性CDK12的选择性抑制可降低DNA损伤修复基因的表达，但内源性CDK12的选择性抑制却很困难。在这里，我们报告MFH290，CDK12 / 13的新型半胱氨酸（Cys）定向共价抑制剂的发展。MFH290与CDK12的Cys-1039形成共价键，表现出优异的激酶组选择性，抑制RNA聚合酶II（Pol II）C端结构域（CTD）中丝氨酸2的磷酸化，并降低关键DNA的表达损伤修复基因。重要的是，这些作用被证明是依赖CDK12的，因为Cys-1039的突变使该激酶对MFH290无效，并恢复了Pol II CTD磷酸化和DNA损伤修复基因的表达。与其对DNA损伤修复基因表达的影响一致，

更新日期：2020-07-09

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