| Summary: | With the findings in anticancer and antiretroviral research, it is strongly believed that CDK9 inhibition would be a useful therapeutic strategy in these fields. A number of pharmacological CDK inhibitors have been previously reported and are undergoing preclinical and clinical evaluation, but none of them selectively targets CDK9. In this project, a number of anilino-4-(thiazol-5-yl)pyrimidine derivatives have been successfully prepared. The most potent compound exhibited best potency with GIso around 10 nM. A set of compounds were tested against CDKl, 2, 7 and 9 and the preliminary structure-activity relationship was established. More than a dozen compounds showed excellent CDK9 inhibitory activity with Ki lower than 10 nM. Lead compound 29, 52 and 67 showed different profile of selectivity towards CDK9, with 21, 6 and 7 nM Ki respectively. Cellular mode of action of lead compound 29 was investigated and the correlation between CDK9 inhibition and anti-tumor activity was confirmed. In the CLL cytotoxicity assay, comparing with clinical compound flavopiridol, compound 52 showed significant selectivity advantage toward norinal B and T-cells against CLL B-cells, which is more than WOO-fold. Several lead compounds, like 52 and 69, are currently scheduled for in vivo assessment. Further research on the basis of this project will result in lead drug candidates for potential cancer therapy.
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