Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors.
Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors.
复制标题
克服对一系列共价转录CDK抑制剂的抗性。
DOI：
10.1016/j.chembiol.2017.11.007
复制
发表时间：
2018-02-15
影响因子：
8.6
通讯作者：
George RE
中科院分区：
文献类型：
--
作者：
Gao Y;Zhang T;Terai H;Ficarro SB;Kwiatkowski N;Hao MF;Sharma B;Christensen CL;Chipumuro E;Wong KK;Marto JA;Hammerman PS;Gray NS;George RE
转录细胞周期蛋白依赖性激酶 (CDK) 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它们的临床发展。在这里，我们证明多药转运蛋白 ABCB1 和 ABCG2 的上调是对 THZ1 耐药的主要模式，THZ1 是神经母细胞瘤和肺癌中 CDK 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，确定它通过共价修饰 CDK12 的半胱氨酸 1039 发挥其细胞毒性作用。这些结果强调了在 THZ1 临床类似物开发中考虑这种常见耐药模式的重要性，鉴定了一种不易受 ABC 转运蛋白介导的药物流出影响的共价 CDK12 抑制剂，并证明可以通过耐药性选择来完成靶点解卷积。高等人。报告 ABC 转运蛋白上调是对 THZ 系列共价 CDK7/12/13 抑制剂获得性耐药的主要机制，并描述了 E9 的产生，E9 逃避药物外流，其靶点选择性通过在 E9 耐药细胞中获得 CDK12 结合位点突变得到证实。
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 transportermediated drug efflux, and demonstrate that target deconvolution can be accomplished through selection for resistance. Gao et al. report ABC transporter upregulation as a major mechanism of acquired resistance to the THZ series of covalent CDK7/12/13 inhibitors and describe the generation of E9, which escapes drug efflux and whose target selectivity was confirmed by the acquisition of a CDK12-binding site mutation in E9-resistant cells.
登录
查看更多内容
影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
3.2
作者：
Gorlick R;Kolb EA;Houghton PJ;Morton CL;Neale G;Keir ST;Carol H;Lock R;Phelps D;Kang MH;Reynolds CP;Maris JM;Billups C;Smith MA
通讯作者：
Smith MA
影响因子：
--
作者：
Miduturu CV;Deng X;Kwiatkowski N;Yang W;Brault L;Filippakopoulos P;Chung E;Yang Q;Schwaller J;Knapp S;King RW;Lee JD;Herrgard S;Zarrinkar P;Gray NS
通讯作者：
Gray NS
影响因子：
14.8
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.
通讯作者：
Gray, Nathanael S.
影响因子：
3
作者：
Parikh JR;Askenazi M;Ficarro SB;Cashorali T;Webber JT;Blank NC;Zhang Y;Marto JA
通讯作者：
Marto JA