Liu Qingsong and Liu Jing, research group of strong magnetic field center of Chinese Academy of Sciences, developed a new type of CDK9 kinase inhibitor with high selectivity and activity

Recently, researchers Liu Qingsong and Liu Jing from the strong magnetic field science center of the Chinese Academy of sciences have developed a highly selective new CDK9 kinase inhibitor jsh-150 in CDK family kinases, which has the potential to become a broad-spectrum anti-tumor targeting drug The research results were published online in European Journal of Medical Chemistry (DOI: 10.1016 / j.ejmech 2018.09.025) As a subunit of P-TEFb, cyclin-dependent kinase 9 (CDK9) plays an important role in the transcription process CDK9 kinase regulates RNA transcription of short-lived antiapoptotic protein, so it is an important target in many cancers Due to the large number of CDK family members, there are more than 20 subtypes of CDK with high conservation and spatial structure similarity, leading to the low selectivity of many CDK9 inhibitors at present, resulting in off target toxic side effects Therefore, the development of CDK9 inhibitors with high selectivity and activity is of great significance for basic research and clinical application In this work, the researchers developed jsh-150, a highly selective and active CDK9 kinase inhibitor, by analyzing the structure of CDK9 kinase and adopting the concept of structure-based drug design The experimental results show that jsh-150 has good selectivity in CDK family members The activity of jsh-150 to CDK9 is 300-10000 times of that to other members of CDK family, and it can effectively inhibit the activity of CDK9 kinase (IC50 = 1nm) In addition, the results of binding strength test with other 468 kinases showed that jsh-150 also had high selectivity in the kinase group Jsh-150 has a strong anti proliferation effect in different cancer cell lines, such as melanoma, squamous cell carcinoma, gastrointestinal stromal tumor, colorectal cancer, B-cell lymphoma, acute myeloid leukemia and chronic lymphoid leukemia, which initially shows its potential of broad-spectrum anti-tumor activity In addition, the antitumor activity of the drug in vivo was tested on the subcutaneous transplanted tumor model of acute myeloid leukemia cell mv4-11, and jsh-150 showed a good inhibitory effect on the tumor at the dose of 20 mg / kg The research work is mainly completed by postdoctoral Wu Yun, doctoral students Wang Beilei, Wu Jiaxin, Chen Cheng, assistant researcher Zou Fengming, etc The research was supported by NSFC, the top talent program of 10000 Talents Program for young people, the key research program of Frontier Science of Chinese Academy of Sciences, China Postdoctoral fund and Anhui Natural Science Fund.