Cheng Sha-Sha, Qu Yuan-Qing, Wu Jia, Yang Guan-Jun, Liu Hao, Wang Wanhe, Huang Qi, Chen Feng, Li Guodong, Wong Chun-Yuen, Wong Vincent Kam Wai, Ma Dik-Lung, Leung Chung-Hang
Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China.
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.
Acta Pharm Sin B. 2022 Mar;12(3):1390-1405. doi: 10.1016/j.apsb.2021.10.024. Epub 2021 Oct 30.
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 bound to CDK9 an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction and . Importantly, complex showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.
细胞周期蛋白依赖性激酶9（CDK9）的活性与三阴性乳腺癌（TNBC）患者的不良预后相关。CDK9与细胞周期蛋白T1之间的异二聚体对于维持激酶的活性状态至关重要，靶向这种蛋白质-蛋白质相互作用（PPI）可能为选择性抑制CDK9提供有前景的途径。在此，我们设计并生成了一个带有7-氯-2-苯基喹啉CˆN配体的金属配合物文库，并测试了它们对CDK9-细胞周期蛋白T1 PPI的活性。配合物 以焓驱动的结合模式与CDK9结合，导致CDK9-细胞周期蛋白T1相互作用的破坏 以及 。重要的是，配合物 在小鼠体内对TNBC同种异体移植瘤显示出有前景的抗转移活性，并且与顺铂相比具有相当的活性。据我们所知， 是首个对TNBC具有抗转移活性的CDK9-细胞周期蛋白T1 PPI抑制剂。配合物 可作为未来设计针对包括TNBC在内的癌症更有效激酶抑制剂的新平台。
