The synthesis of PROTAC molecule and new target KAT6A identification of CDK9 inhibitor i CDK9  

作　　者：Mingtao Ao Jun Wu Yin Cao Yaohui He Yuxiang Zhang Xiang Gao Yuhua Xue Meijuan Fang Zhen Wu 

机构地区：[1]Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology,School of Pharmaceutical Sciences,Xiamen University,Xiamen 361102,China [2]School of Pharmacy,Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province,Hubei University of Science and Technology,Xianning 437100,China

出　　处：《Chinese Chemical Letters》2023年第4期216-221,共6页中国化学快报（英文版）

基　　金：supported by grants from the National Key R&D Program of China (Nos. 2018YFA0107303 and 2020YFA0908100);the National Natural Science Foundation of China (Nos. 81773600and 82102746);the China Postdoctoral Science Foundation (No.2021M690095);the Fundamental Research Funds for the Central Universities (No. 20720180051)。

摘　　要：Cyclin-dependent kinases(CDKs) have become potential targets for treating various diseases, especially cancer. Compound i CDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential toxicity and poor understanding of the underlying mechanism. The PROTAC(proteolysis targeting chimera) degraders of bioactive molecules can significantly induce in vitro and in vivo degradation of their target protein with high selectivity and effectively reduce the dose-limiting toxicity of small molecule drugs. Therefore, we designed and synthesized the bifunctional PROTAC molecules of i CDK9, being used for identifying its previously unknown target and revealing the underlying pharmacological mechanism.The PROTAC bifunctional molecule CD-5 could selectively and significantly degrade CDK9 with low cell toxicity. Therefore, we selected CD-5 as a chemical prober in the SILAC quantitative proteomic analysis, which disclosed that CD-5 could enormously lessen the lysine acetyltransferase KAT6A. Furthermore,KAT6A degradation induced by CD-5 repressed the levels of H3K14Ac and H3K23Ac. Lastly, the streptavidin immunoprecipitation(IP) assay confirmed a direct interaction between KAT6A and i CDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of i CDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules.

关 键 词：PROTAC SILAC iCDK9 KAT6A Target identification 

分 类 号：TQ460.1[化学工程—制药化工]