期刊
ACTA PHARMACEUTICA SINICA B
卷 12, 期 3, 页码 1390-1405出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.10.024
关键词
Metal complex; Kinase inhibitor; Protein-protein interaction; Epigenetics; Triple-negative breast cancer; Metastasis
资金
- Hong Kong Baptist University
- Health and Medical Research Fund [HMRF/14150561]
- National Natural Science Foundation of China [22077109, 21775131]
- Science and Technology Development Fund, Macau SAR [0007/2020/A]
- SKL-QRCM (UM) - 2020-2022
- University of Macau, China [MYRG2019-00002-ICMS]
- Foshan Medicine Dengfeng Project of China (2019-2021)
- 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab, China) [2020B1212030006]
CDK9 inhibition is a potential therapeutic strategy for TNBC, and compound 1 demonstrates promising anti-metastatic activity.
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. (c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据