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Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2017-12-21 , DOI: 10.1016/j.chembiol.2017.11.007 Yang Gao 1 , Tinghu Zhang 2 , Hideki Terai 3 , Scott B Ficarro 4 , Nicholas Kwiatkowski 2 , Ming-Feng Hao 2 , Bandana Sharma 5 , Camilla L Christensen 3 , Edmond Chipumuro 6 , Kwok-Kin Wong 3 , Jarrod A Marto 4 , Peter S Hammerman 3 , Nathanael S Gray 7 , Rani E George 1
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2017-12-21 , DOI: 10.1016/j.chembiol.2017.11.007 Yang Gao 1 , Tinghu Zhang 2 , Hideki Terai 3 , Scott B Ficarro 4 , Nicholas Kwiatkowski 2 , Ming-Feng Hao 2 , Bandana Sharma 5 , Camilla L Christensen 3 , Edmond Chipumuro 6 , Kwok-Kin Wong 3 , Jarrod A Marto 4 , Peter S Hammerman 3 , Nathanael S Gray 7 , Rani E George 1
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Irreversible inhibition of transcriptional cyclin-dependent kinases (CDKs) provides a therapeutic strategy for cancers that rely on aberrant transcription; however, lack of understanding of resistance mechanisms to these agents will likely impede their clinical evolution. Here, we demonstrate upregulation of multidrug transporters ABCB1 and ABCG2 as a major mode of resistance to THZ1, a covalent inhibitor of CDKs 7, 12, and 13 in neuroblastoma and lung cancer. To counter this obstacle, we developed a CDK inhibitor, E9, that is not a substrate for ABC transporters, and by selecting for resistance, determined that it exerts its cytotoxic effects through covalent modification of cysteine 1039 of CDK12. These results highlight the importance of considering this common mode of resistance in the development of clinical analogs of THZ1, identify a covalent CDK12 inhibitor that is not susceptible to ABC transporter-mediated drug efflux, and demonstrate that target deconvolution can be accomplished through selection for resistance.
中文翻译：
克服对THZ系列共价转录CDK抑制剂的抗性。
转录细胞周期蛋白依赖性激酶（CDKs）的不可逆抑制为依赖异常转录的癌症提供了一种治疗策略。然而，缺乏对这些药物耐药机制的了解可能会阻碍其临床发展。在这里，我们证明了多药转运蛋白ABCB1和ABCG2的上调是对THZ1的主要抵抗方式，THZ1是成神经细胞瘤和肺癌中CDKs 7、12和13的共价抑制剂。为了克服这一障碍，我们开发了一种CDK抑制剂E9，它不是ABC转运蛋白的底物，并通过选择抗性来确定其通过共价修饰CDK12的半胱氨酸1039发挥其细胞毒性作用。这些结果突显了在开发THZ1临床类似物时考虑这种常见耐药模式的重要性，
更新日期：2018-02-15
中文翻译：
克服对THZ系列共价转录CDK抑制剂的抗性。
转录细胞周期蛋白依赖性激酶（CDKs）的不可逆抑制为依赖异常转录的癌症提供了一种治疗策略。然而，缺乏对这些药物耐药机制的了解可能会阻碍其临床发展。在这里，我们证明了多药转运蛋白ABCB1和ABCG2的上调是对THZ1的主要抵抗方式，THZ1是成神经细胞瘤和肺癌中CDKs 7、12和13的共价抑制剂。为了克服这一障碍，我们开发了一种CDK抑制剂E9，它不是ABC转运蛋白的底物，并通过选择抗性来确定其通过共价修饰CDK12的半胱氨酸1039发挥其细胞毒性作用。这些结果突显了在开发THZ1临床类似物时考虑这种常见耐药模式的重要性，
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