Citation: Mingtao Ao, Jun Wu, Yin Cao, Yaohui He, Yuxiang Zhang, Xiang Gao, Yuhua Xue, Meijuan Fang, Zhen Wu. The synthesis of PROTAC molecule and new target KAT6A identification of CDK9 inhibitor iCDK9[J]. Chinese Chemical Letters, ;2023, 34(4): 107741. doi: 10.1016/j.cclet.2022.107741 shu

The synthesis of PROTAC molecule and new target KAT6A identification of CDK9 inhibitor iCDK9

Mingtao Ao ^{a, b, 1} ,
Jun Wu ^{a, 1} ,
Yin Cao ^a ,
Yaohui He ^a ,
Yuxiang Zhang ^a ,
Xiang Gao ^a ,
Yuhua Xue ^{a, *,} ,
Meijuan Fang ^{a, *,} ,
Zhen Wu ^{a, *,}

a.
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
b.
School of Pharmacy, Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning 437100, China

xueyuhua@xmu.edu.cn

fangmj@xmu.edu.cn

wuzhen@xmu.edu.cn

Received Date: 29 April 2022
Revised Date: 6 August 2022
Accepted Date: 10 August 2022
Available Online: 14 August 2022

Figures(6)

Cyclin-dependent kinases (CDKs) have become potential targets for treating various diseases, especially cancer. Compound iCDK9 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 iCDK9, 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 iCDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of iCDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules.
- PROTAC,
- SILAC,
- iCDK9,
- KAT6A,
- Target identification
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