915070-01-8Relevant articles and documents
Protein kinase inhibitor and derivatives thereof, preparation method and application thereof, and pharmaceutical composition
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Paragraph 0117-0120, (2021/10/27)
The invention discloses a protein kinase inhibitor and derivatives thereof, a preparation method and application thereof, and a pharmaceutical composition . The compound structure of the protein kinase inhibitor is shown in a formula (I), and the protein kinase inhibitor derivatives relate to an isomer, a diastereoisomer, an enantiomer, a tautomer, a solvate, a salt of the solvate, a pharmaceutically acceptable salt or a mixture of the isomer, the diastereoisomer, the enantiomer, the tautomer, the solvate, the salt of the solvate and the pharmaceutically acceptable salt of the protein kinase inhibitor. The protein kinase inhibitor and the derivatives thereof have an efficient inhibition effect on protein kinase, can reduce or inhibit the activity of the protein kinase in cells, and can be used for preparing drugs for treating and/or preventing hyperproliferative diseases, virus-induced infectious diseases and/or cardiovascular diseases, and the compound synthesis method is simple and easy to operate.
Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity
Chen, Yadong,Dong, Ruinan,Duan, Chunqi,Huang, Jianhang,Jiang, Fei,Li, Hongmei,Li, Shuwen,Liu, Chenhe,Lu, Tao,Tang, Weifang,Wang, Xinren,Xu, Junyu,Zhang, Tianyi,Zhang, Yanmin,Zhu, Gaoyuan,Zhu, Yuqin
, (2020/05/22)
Specific inhibition of CDK9 is considered a promising strategy for developing effective anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 inhibitor with high selectivity (8300-fold over CDK7). Binding mode analysis illustrated that the substituent coumarin moiety is a critical group for CDK9 selectivity by occupying a flexible hinge/αD region, which is sterically hindered in other CDKs. Compound 30i showed excellent cellular antiproliferative activity, moderate pharmacokinetic property and low hERG inhibition. Moreover, 30i significantly induced tumour growth inhibition in a dose-dependent manner without causing an obvious loss of body weight in an MV4-11 xenograft mice model. Altogether, these results suggest that 30i may serve as a potential acute myeloid leukaemia (AML) therapeutics by selectively targeting CDK9.
