Kuchukulla, Ratnakar Reddy Hwang, Injeoung Kim, Suhn Hyung Kye, Younghyeon Park, NaRae Cha, Heary Moon, Sojeong Chung, Hwan Won Lee, Cheolju Kong, Gu Hur, Woo young 2024-01-23T08:30:53Z 2024-01-23T08:30:53Z 2024-01-23 2024-01 0223-5234 https://pubs.kist.re.kr/handle/201004/148446 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. English Elsevier BV Identification of a novel potent CDK inhibitor degrading cyclinK with a superb activity to reverse trastuzumab-resistance in HER2-positive breast cancer in vivo Article 10.1016/j.ejmech.2023.116014 1 European Journal of Medicinal Chemistry, v.264 European Journal of Medicinal Chemistry 264 N scie scopus 001139134700001 Chemistry, Medicinal Pharmacology & Pharmacy Article DISCOVERY JIMT-1 EXPRESSION MUTATIONS HER2-positive breast cancer Trastuzumab-resistance CDK12 inhibitor CyclinK degrader Dinaciclib