Hefei Research Institute developed a new highly selective and highly active CDK9 kinase inhibitor
September 29, 2018 Source: Hefei Institute of Material Science, Chinese Academy of Sciences
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Recently, Liu Qingsong and Liu Jing, researchers of the Strong Magnetic Field Science Center of the Hefei Institute of Material Science, Chinese Academy of Sciences, have developed a highly selective novel CDK9 kinase inhibitor JSH-150 in the CDK family of kinases, which has the potential to become a broad-spectrum anti-tumor target. To the drug. The research results are published online in the Journal of Medicinal Chemistry, European Journal of Medicinal Chemistry (doi: 10.1016/j.ejmech.2018.09.025).
Cyclin-dependent kinase 9 (CDK9), a subunit of p-TEFb, is involved in the elongation of transcription and plays an important role in the transcription process. CDK9 kinase regulates RNA transcription of short-lived anti-apoptotic proteins, and thus it is an important target for action in a variety of cancers. Due to the large number of members of the CDK kinase family, there are highly conserved and spatial structural similarities between sequences of more than 20 subtypes, resulting in the current low selectivity of many CDK9 inhibitors, resulting in off-target toxic side effects. Therefore, the development of highly selective and highly active CDK9 inhibitors is of great significance for basic research as well as clinical applications.
In this work, the researchers developed a highly selective, highly active CDK9 kinase inhibitor, JSH-150, by analyzing the structure of the CDK9 kinase and using a structure-based drug design concept. The results showed that JSH-150 achieved good selectivity in CDK family members. JSH-150 is 300-10000 times more active against CDK9 than other CDK family members, and it can effectively inhibit CDK9 kinase activity (IC50 = 1 nM). ).
In addition, the binding strength test results with other 468 kinases showed that JSH-150 was also highly selective in the kinase group. JSH-150 shows strong resistance in different cancer cell lines such as melanoma, squamous cell carcinoma, gastrointestinal stromal tumor, colorectal cancer, B cell lymphoma, acute myeloid leukemia and chronic lymphocytic leukemia cell lines. Proliferation has initially demonstrated its potential for broad-spectrum anti-tumor activity. In addition, the in vivo antitumor activity of the drug was tested on a mouse subcutaneous xenograft model of acute myeloid leukemia cell MV4-11, and JSH-150 showed a good inhibitory effect on the tumor at a dose of 20 mg/kg.
The research work was mainly completed by postdoctoral Wu Yun, Ph.D. students Wang Yulei, Wu Jialu, Chen Cheng, and assistant researcher Zou Fengming. The research was supported by the National Natural Science Foundation of China, the Young Talents Program of the 10,000 Plan, the Key Research Project of the Frontier Science of the Chinese Academy of Sciences, the China Postdoctoral Fund and the Natural Science Foundation of Anhui Province.
Biological Characterization of JSH-150 (compd. 40) and Its Anti-tumor Effect on Mouse Model of MV4-11 Tumor Cells
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