Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13
Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13
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DOI：
10.1021/acs.jmedchem.9b01929
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发表时间：
2020-07-09
影响因子：
7.3
通讯作者：
Gray, Nathanael S.
中科院分区：
文献类型：
--
作者：
Liu, Yao;Hao, Mingfeng;Gray, Nathanael S.
细胞周期蛋白依赖性激酶 12 (CDK12) 的基因缺失或类似物敏感的 CDK12 的选择性抑制可减少 DNA 损伤修复基因的表达，但内源性 CDK12 的选择性抑制很困难。在此，我们报告了 MFH290 的开发，这是一种新型半胱氨酸 (Cys) 定向的 CDK12/13 共价抑制剂。 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 末端结构域 (CTD) 中丝氨酸 2 的磷酸化，并减少关键 DNA 损伤修复基因的表达。重要的是，这些效应被证明是 CDK12 依赖性的，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 损伤修复基因表达。与其对 DNA 损伤修复基因表达的作用一致，MFH290 增强了 PARP 抑制剂奥拉帕尼的抗增殖作用。
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.