细胞周期蛋白依赖性激酶9（CDK9）的表达水平和激酶活性的异常与急性髓系白血病（AML）易复发特点密切相关。开发高效低毒的新型CDK9抑制剂对于AML治疗具有重要意义。本项目前期通过合理药物设计获得新型靶向CDK9的小分子抑制剂1705，其对CDK9抑制活性达到纳摩尔级，并在体内外表现出良好的抗肿瘤活性及安全性。本项目拟以1705为先导物，分析其与CDK9蛋白结合模式，结合化学信息学及化学生物学等技术对其进行更为全面的结构改造，深入探究“构-效”关系。此外，为克服其存在的多羟基、母环骨架过于刚性等类药效问题，将在最优骨架基础上进行功能取代基配置方案的探索，以期得到高效、低毒、具有类药性的全新骨架的CDK9抑制剂作为抗AML候选新药。同时，本项目将对活性最优的小分子抑制剂进行生物机制学研究以探究CDK9在AML治疗领域的相关生物学信息，为后续小分子抑制剂的研究提供理论依据及参考

Cyclin-dependent kinase 9 is one of the most crucial molecule in the cancer cells in the development of tumorigenesis. It is found that CDK9 is deregulated in most malignancies and is frequently upregulated in acute myelocytic leukemia (AML). Therefore, CDK9 inhibitors have elicited great interest in AML to discover novel anticancer therapeutics. Our research group has recently discovered novel inhibitor 1705 of CKD9. The compound showed strong inhibition of CDK9 with IC50 at nanomolar and was found to be potent and highly selective for cancer cells in in vitro and in vivo. Taking this compound as lead compound, we further carried on the structure-activity relationship (SAR) and structure-property relationship (SPR) studies to obtain compounds with improved specificity, drug-like property and safety. During the process, we using comprehensive technologies combined with rational drug design study, molecular informatics study and chemical biology study. We are expected to discover novel CDK9 inhibitors as promising antitumor candidates. In addition, the most promising compound would be employed for further biological mechanism study to explore the correlation between CDK9 and AML. The conclusion could be reference for the next generation CDK9 inhibitors.