Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents

被引：15
|
作者：
Shao, Hao [1 ]
Foley, David W. [1 ]
Huang, Shiliang [1 ]
Abbas, Abdullahi Y. [1 ]
Lam, Frankie [2 ]
Gershkovich, Pavel [1 ]
Bradshaw, Tracey D. [1 ]
Pepper, Chris [3 ]
Fischer, Peter M. [1 ]
Wang, Shudong [1 ,2 ]
机构：
[1] Univ Nottingham, Sch Pharm & Biodiscovery Inst, Univ Pk, Nottingham NG7 2RD, England
[2] Univ South Australia, Clin & Hlth Sci, Drug Discovery & Dev, Adelaide, SA 5001, Australia
[3] Univ Sussex, Brighton & Sussex Med Sch, Brighton BN1 9PX, E Sussex, England
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 214卷
关键词：
RNA polymerase II; CDK9; inhibitor; Apoptosis; Mcl-1; Chronic lymphocytic leukaemia; Anti-Cancer agents; GENE-EXPRESSION; CANCER; FLUORINE; FLAVOPIRIDOL; TARGETS; MCL-1;
D O I：
10.1016/j.ejmech.2021.113244
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Cyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the conserved ATP binding site, designing selective CDK9 inhibitors has been challenging. Here we report our continued efforts in the optimization of 2,4,5-tri-substituted pyrimidine compounds as potent and selective CDK9 inhibitors. The most selective compound 30m was >100-fold selective for CDK9 over CDK1 and CDK2. These compounds showed broad anti-proliferative activities in various solid tumour cell lines and patient-derived chronic lymphocytic leukaemia (CLL) cells. Decreased phosphorylation of the carboxyl terminal domain (CTD) of RNAPII at Ser-2 and down-regulation of anti-apoptotic protein Mcl-1 were confirmed in both the ovarian cancer model A2780 and patient-derived CLL cells. (C) 2021 Elsevier Masson SAS. All rights reserved.
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页数：15
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