Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer

作     者：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 

作者机构：Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese MedicineUniversity of MacaoMacao 999078China Dr.Neher’s Biophysics Laboratory for Innovative Drug DiscoveryState Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao 999078China State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-productsNingbo UniversityKow loon TongHong Kong 999077China Laboratory of Biochemistry and Molecular BiologySchool of Marine SciencesNingbo UniversityNingbo 315211China Department of ChemistryHong Kong Baptist UniversityNingbo 315211China Institute of Medical ResearchNorthwestern Polytechnical UniversityXi'an 710072China Department of ChemistryCity University of Hong KongHong Kong 999077China Department of Biomedical SciencesFaculty of Health SciencesUniversity of MacaoMacao 999078China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第3期

页      面：1390-1405页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：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,Macao SAR(File no.0007/2020/A),SKL-QRCM(UM)-20202022 the University of Macao(MYRG2019-00002-ICMS,China) Foshan Medicine Dengfeng Project of China(2019-2021) 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong KongMacao Joint Lab,No:2020B1212030006,China) 

主　　题：Metal complex Kinase inhibitor Protein-protein interaction Epigenetics Triple-negative breast cancer Metastasis 

摘      要：Cyclin-dependent kinase 9(CDK9) activity is correlated with worse outcomes of triplenegative 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 CDK9cyclin 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.