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

  • Acta Pharm Sin B. 2022 Mar;12(3):1390-1405. doi: 10.1016/j.apsb.2021.10.024.
Sha-Sha Cheng  1 ,  Yuan-Qing Qu  2 ,  Jia Wu  1 ,  Guan-Jun Yang  1  3  4 ,  Hao Liu  5 ,  Wanhe Wang  5  6 ,  Qi Huang  2 ,  Feng Chen  1 ,  Guodong Li  1 ,  Chun-Yuen Wong  7 ,  Vincent Kam Wai Wong  2 ,  Dik-Lung Ma  5 ,  Chung-Hang Leung  1  8
Affiliations
  • 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. State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo 315211, China.
  • 4. Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China.
  • 5. Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China.
  • 6. Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China.
  • 7. Department of Chemistry, City University of Hong Kong, Hong Kong 999077, China.
  • 8. Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao 999078, China.
PMID: 35530158 DOI: 10.1016/j.apsb.2021.10.024
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.

Keywords
Epigenetics; Kinase inhibitor; Metal complex; Metastasis; Protein–protein interaction; Triple-negative breast cancer.
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