Fluorocyclopropyl-Containing Tacrine Derivatives as Potent and Selective Dual CDK2/CDK9 Inhibitors for the Treatment...

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.