曲妥珠单抗
细胞周期蛋白依赖激酶
癌症研究
CDK抑制剂
化学
基诺美
体内
乳腺癌
生长抑制
药理学
细胞生长
激酶
癌症
内科学
生物
医学
细胞周期
生物化学
生物技术
作者
Ratnakar Reddy Kuchukulla,Injeoung Hwang,Suhn Hyung Kim,Young-Hyeon Kye,Narae Park,Hyo-Jeong Cha,Sojeong Moon,Hwan Won Chung,Cheolju Lee,Gu Kong,Wooyoung Hur
标识
DOI:10.1016/j.ejmech.2023.116014
摘要
CDK12 is overexpressed in HER2-positive breast cancers and promotes tumorigenesis and trastuzumab resistance. Thus CDK12 is a good therapeutic target for the HER2-positive breast tumors resistant to trastuzumab. We previously reported a novel purine-based CDK inhibitor with an ability to degrade cyclinK. Herein, we further explored and synthesized new derivatives, and identified a new potent pan-CDK inhibitor degrading cyclinK (32e). Compound 32e potently inhibited CDK12/cyclinK with IC50 = 3 nM, and suppressed the growth of the both trastuzumab-sensitive and trastuzumab-resistant HER2-positive breast cancer cell lines (GI50's = 9–21 nM), which is superior to a potent, clinical pan-CDK inhibitor dinaciclib. Moreover, 32e (10, 20 mg/kg, ip, twice a week) showed a dose-dependent inhibition of tumor growth and a more dramatic anti-cancer effect than dinaciclib in mouse in vivo orthotopic breast cancer model of trastuzumab-resistant HCC1954 cells. Kinome-wide inhibition profiling revealed that 32e at 1 μM exhibits a decent selectivity toward CDK-family kinases including CDK12 over other wildtype protein kinases. Quantitative global proteomic analysis of 32e-treated HCC1954 cells demonstrated that 32e also showed a decent selectivity in degrading cyclinK over other cyclins. Compound 32e could be developed as a drug for intractable trastuzumab-resistant HER2-positive breast cancers. Our current study would provide a useful insight in designing potent cyclinK degraders.
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