Discovery of novel and potent tacrine derivatives as CDK2 inhibitors. (24th October 2022) - Huang, Yaoguang
Abstract : After optimization of the lead compound, ZLHT-7, a compound with 10-fold higher selectivity for CDK2 over CDK9, was discovered. Abstract : Cycle-dependent kinases (CDKs) play crucial and extensive roles in cellular processes. CDK2, one of the most well-studied members of this group, controls the course of the cell cycle and is correlated with the development of tumors. Tacrine was the first drug to treat Alzheimer's disease, and despite failing in hepatotoxicity, its novel skeleton has been used for drug design. Previously, we designed and synthesized tacrine derivatives for cancer therapeutics using the inhibitory properties of CDKs. In this paper, we enhanced the selectivity of CDK2 over CDK9 by adjusting their hydrophobic regions. Eventually, ZLHT-7, a compound with 10-fold higher selectivity for CDK2 over CDK9, was screened out of the 19 compounds synthesized. Preliminary pharmacological experiments revealed that it arrests the cell cycle in the S phase and triggers cell apoptosis. This endeavor also investigated the effect of the hydrophobic edge region structure on CDK2 and CDK9 activities, paving the way for the design of highly selective CDK2 inhibitors.