Limeng Wu, Wenjie Liu, Wenjie Liu, Xinyue Ning, Xinyu Li, Zhiya Wang, Yiming Qi, Yiming Qi, Jiao Xiao, Xiangbo Xu, Xudong Gao, Xinhua Liu, Yingshi Zhang, Zihua Xu, Yonghong Liu, Wenwu Liu, Yonghong Liu, Qingchun Zhao
Abstract CDK2 and CDK9 play critical roles in cell cycle progression and transcriptional regulation, respectively. And CDK2/9 are highly expressed in colorectal cancer (CRC), which dysregulation contributes significantly to CRC pathogenesis. Through structure-based drug design strategy we have identified ZLMT-72, a fluorocyclopropyl-containing tacrine derivative as a dual CDK2/9 inhibitor. Biological assay results indicated that ZLMT-72 exhibited potent inhibitory activity against both CDK2 (IC50 = 0.741 nM) and CDK9 (IC50 = 1.03 nM), demonstrating strong antiproliferative effects in the CRC cell line HCT116 (GI50 < 0.1 nM). Kinase profiling and cholinesterase inhibition assays confirmed a primary and potent inhibitory activity of ZLMT-72 against CDK2/9. Importantly, ZLMT-72 (10 mg/kg) displayed robust antitumor efficacy in both subcutaneous (TGI = 50.6%) and orthotopic (TGI = 84.3%) xenograft tumor models of HCT116, alongside favorable pharmacokinetic properties and a promising safety profile. Collectively, ZLMT-72, as a potent dual CDK2/9 inhibitor, holds substantial therapeutic potential for CRC treatment.