Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer.
10.1016/j.apsb.2021.10.024
- Author:
Sha-Sha CHENG
1
;
Yuan-Qing QU
2
;
Jia WU
1
;
Guan-Jun YANG
1
;
Hao LIU
3
;
Wanhe WANG
3
;
Qi HUANG
2
;
Feng CHEN
1
;
Guodong LI
1
;
Chun-Yuen WONG
4
;
Vincent Kam Wai WONG
2
;
Dik-Lung MA
3
;
Chung-Hang LEUNG
1
Author Information
1. Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China.
2. 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.
3. Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China.
4. Department of Chemistry, City University of Hong Kong, Hong Kong 999077, China.
- Publication Type:Journal Article
- Keywords:
Epigenetics;
Kinase inhibitor;
Metal complex;
Metastasis;
Protein–protein interaction;
Triple-negative breast cancer
- From:
Acta Pharmaceutica Sinica B
2022;12(3):1390-1405
- CountryChina
- Language:English
-
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 CˆN 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.
