期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 66, 期 8, 页码 5439-5452出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01718
关键词
-
Cyclin-dependent kinase 8 (CDK8), a kinase subunit of the Mediator complex, is involved in regulating RNA polymerase II-mediated transcription and plays a role in oncogenic control. CDK8 deregulation is associated with human diseases, particularly acute myeloid leukemia (AML) and advanced solid tumors. In this study, an azaindole series of CDK8 inhibitors were successfully optimized using a structure-based generative chemistry approach. Compound 23, the most promising inhibitor, demonstrated robust tumor growth inhibition in multiple in vivo models after oral administration.
Cyclin-dependent kinase 8 (CDK8), as a kinase subunit of the Mediator complex, is involved in the regulation of RNA polymerase II-mediated transcription, thereby modulating multiple signaling pathways and multiple transcription factors involved in oncogenic control. CDK8 deregulation has been implicated in human diseases, particularly in acute myeloid leukemia (AML) and advanced solid tumors, where it has been reported as a putative oncogene. Here, we report the successful optimization of an azaindole series of CDK8 inhibitors that were identified and further progressed through a structure-based generative chemistry approach. In several optimization cycles, we improved in vitro microsomal stability, kinase selectivity, and in vivo pharmacokinetic profile cross-species, leading to the discovery of compound 23, which demonstrated robust tumor growth inhibition in multiple in vivo efficacy models after oral administration.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据