Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation.
Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation.
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DOI：
10.1038/nchembio.2538
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发表时间：
2018-03
影响因子：
14.8
通讯作者：
Gray NS
中科院分区：
文献类型：
--
作者：
Olson CM;Jiang B;Erb MA;Liang Y;Doctor ZM;Zhang Z;Zhang T;Kwiatkowski N;Boukhali M;Green JL;Haas W;Nomanbhoy T;Fischer ES;Young RA;Bradner JE;Winter GE;Gray NS
细胞周期蛋白依赖性激酶9（CDK 9）是转录延伸的关键调节因子，是癌症治疗的有希望的靶点，特别是对于由转录失调驱动的癌症。在此，我们报告了NVP-2（3）（一种选择性ATP竞争性CDK 9抑制剂）和THAL-SNS-032（一种选择性CDK 9降解剂，由CDK结合SNS-032配体与沙利度胺衍生物连接组成，该衍生物结合E3泛素连接酶Cereblon（CRBN）。令人惊讶的是，THAL-SNS-032诱导CDK 9的快速降解，而不影响其他SNS-032靶标的水平。此外，由THAL-SNS-032引起的转录变化比由SNS-032诱导的转录变化更像由NVP-2引起的那些。引人注目的是，化合物洗脱没有显著降低THAL-SNS-032诱导的细胞凋亡的水平，表明与CDK 9抑制相比，CDK 9降解具有延长的细胞毒性作用。因此，我们的研究结果表明，沙利度胺缀合代表了将多靶向抑制剂转化为选择性降解剂的有前途的策略，并揭示了激酶降解与抑制相比可以诱导不同的药理学作用。
Cyclin dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. Here, we report the characterization of NVP-2 (3), a selective ATP-competitive CDK9 inhibitor; and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative which binds the E3 ubiquitin ligase Cereblon (CRBN). Surprisingly, THAL-SNS-032 induces rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Strikingly, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared to CDK9 inhibition. Thus, our findings demonstrate thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders, and reveal that kinase degradation can induce distinct pharmacological effects compared to inhibition.
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影响因子：
10.5
作者：
Huang CH;Lujambio A;Zuber J;Tschaharganeh DF;Doran MG;Evans MJ;Kitzing T;Zhu N;de Stanchina E;Sawyers CL;Armstrong SA;Lewis JS;Sherr CJ;Lowe SW
通讯作者：
Lowe SW
影响因子：
--
作者：
Mitra P;Yang RM;Sutton J;Ramsay RG;Gonda TJ
通讯作者：
Gonda TJ
影响因子：
7.3
作者：
Misra, RN;Xiao, HY;Kimball, SD
通讯作者：
Kimball, SD
影响因子：
4.3
作者：
Okuda, Hiroshi;Takahashi, Satoshi;Yokoyama, Akihiko
通讯作者：
Yokoyama, Akihiko
影响因子：
8.8
作者：
Orlando, David A.;Chen, Mei Wei;Guenther, Matthew G.
通讯作者：
Guenther, Matthew G.