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

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

doi:10.1016/j.apsb.2021.10.024

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

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^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal › Journal article › peer-review

37 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1390-1405
Number of pages	16
Journal	Acta Pharmaceutica Sinica B
Volume	12
Issue number	3
Early online date	30 Oct 2021
DOIs	https://doi.org/10.1016/j.apsb.2021.10.024
Publication status	Published - Mar 2022

Scopus Subject Areas

Pharmacology, Toxicology and Pharmaceutics(all)

User-Defined Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.apsb.2021.10.024

Cite this

@article{5808212867f34df5b71ccfe022c1a883,

title = "Inhibition of the CDK9–cyclin T1 protein–protein interaction as a new approach against triple-negative breast cancer",

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",

author = "Cheng, {Sha Sha} and Qu, {Yuan Qing} and Jia Wu and Yang, {Guan Jun} and Hao Liu and Wanhe Wang and Qi Huang and Feng Chen and Guodong Li and Wong, {Chun Yuen} and Wong, {Vincent Kam Wai} and Ma, {Dik Lung} and Leung, {Chung Hang}",

note = "Funding Information: 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). Publisher Copyright: {\textcopyright} 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences",

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language = "English",

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

AU - Cheng, Sha Sha

AU - Qu, Yuan Qing

AU - Wu, Jia

AU - Yang, Guan Jun

AU - Liu, Hao

AU - Wang, Wanhe

AU - Huang, Qi

AU - Chen, Feng

AU - Li, Guodong

AU - Wong, Chun Yuen

AU - Wong, Vincent Kam Wai

AU - Ma, Dik Lung

AU - Leung, Chung Hang

N1 - Funding Information: 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). Publisher Copyright: © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences

PY - 2022/3

Y1 - 2022/3

N2 - 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.

AB - 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.

KW - Epigenetics

KW - Kinase inhibitor

KW - Metal complex

KW - Metastasis

KW - Protein–protein interaction

KW - Triple-negative breast cancer

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U2 - 10.1016/j.apsb.2021.10.024

DO - 10.1016/j.apsb.2021.10.024

M3 - Journal article

AN - SCOPUS:85124675754

SN - 2211-3835

VL - 12

SP - 1390

EP - 1405

JO - Acta Pharmaceutica Sinica B

JF - Acta Pharmaceutica Sinica B

IS - 3

ER -

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

Abstract

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