Original articles
Sha-Sha Cheng, Yuan-Qing Qu, Jia Wu, Guan-Jun Yang, Hao Liu, Wanhe Wang, Qi Huang, Feng Chen, Guodong Li, Chun-Yuen Wong, Vincent Kam Wai Wong, Dik-Lung Ma, Chung-Hang Leung. Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1390-1405

Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer
Sha-Sha Chenga, Yuan-Qing Qub, Jia Wua, Guan-Jun Yanga,d,e, Hao Liuc, Wanhe Wangc,f, Qi Huangb, Feng Chena, Guodong Lia, Chun-Yuen Wongg, Vincent Kam Wai Wongb, Dik-Lung Mac, Chung-Hang Leunga,h
a. Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China;
b. Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China;
c. Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China;
d. State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo 315211, China;
e. Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China;
f. Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China;
g. Department of Chemistry, City University of Hong Kong, Hong Kong 999077, China;
h. Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao 999078, China
Abstract:
Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CN ligand and tested their activity against the CDK9-cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.
Key words:    Metal complex    Kinase inhibitor    Protein-protein interaction    Epigenetics    Triple-negative breast cancer    Metastasis   
Received: 2021-06-23     Revised: 2021-10-10
DOI: 10.1016/j.apsb.2021.10.024
Funds: This research is supported by Hong Kong Baptist University, the Health and Medical Research Fund (HMRF/14150561), the National Natural Science Foundation of China (22077109 and 21775131), the Science and Technology Development Fund, Macau SAR (File no. 0007/2020/A), SKL-QRCM(UM)-2020-2022, the University of Macau (MYRG2019-00002-ICMS, China), Foshan Medicine Dengfeng Project of China (2019-2021), 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab, No:2020B1212030006, China).
Corresponding author: Vincent Kam Wai Wong,E-mai:bowaiwong@gmail.com;Dik-Lung Ma,E-mai:edmondma@hkbu.edu.hk;Chung-Hang Leung,E-mai:duncanleung@um.edu.mo     Email:bowaiwong@gmail.com;edmondma@hkbu.edu.hk;duncanleung@um.edu.mo
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Authors
Sha-Sha Cheng
Yuan-Qing Qu
Jia Wu
Guan-Jun Yang
Hao Liu
Wanhe Wang
Qi Huang
Feng Chen
Guodong Li
Chun-Yuen Wong
Vincent Kam Wai Wong
Dik-Lung Ma
Chung-Hang Leung

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