Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors.
Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors.
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DOI：
10.1038/nchembio.2166
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发表时间：
2016-10
影响因子：
14.8
通讯作者：
Gray, Nathanael S.
中科院分区：
文献类型：
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作者：
Zhang, Tinghu;Kwiatkowski, Nicholas;Olson, Calla M.;Dixon-Clarke, Sarah E.;Abraham, Brian J.;Greifenberg, Ann K.;Ficarro, Scott B.;Elkins, Jonathan M.;Liang, Yanke;Hannett, Nancy M.;Manz, Theresa;Hao, Mingfeng;Bartkowiak, Bartlomiej;Greenleaf, Arno L.;Marto, Jarrod A.;Geyer, Matthias;Bullock, Alex N.;Young, Richard A.;Gray, Nathanael S.
细胞周期蛋白依赖性蛋白激酶12和13(CDK12和13)在基因转录调控中起着重要作用。然而，CDK12和13抑制剂的缺失阻碍了研究它们在健康细胞和癌细胞中被抑制的后果的能力。本文介绍了一种一流的CDK12和13共价抑制剂THZ531的合理设计。与CDK12-Cyclin K的共结晶表明，THZ531不可逆转地靶向位于激活域之外的半胱氨酸。THZ531导致基因表达丧失，同时失去伸长和过度磷酸化的RNA聚合酶II。特别是，THZ531显著降低DNA损伤反应基因和关键的超级增强子相关转录因子基因的表达。与转录扰动一致的是，THZ531显著诱导了细胞凋亡。因此，能够特异性靶向CDK12和CDK13的小分子可能有助于识别特别依赖于其激酶活性的癌症亚型。
Cyclin-dependent kinases 12 and 13 (CDK12 and 13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and 13 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 13 covalent inhibitor, THZ531. Co-crystallization 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 13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.
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