Novel tacrine derivatives as potential CDK9 inhibitors with low cholinesterase inhibitory properties: design, synthesis, and biological evaluation

Abstract

Cyclin-dependent kinase 9 (CDK9) has been identified as an important drug target for the treatment of cancers. Herein, we report the discovery of a series of tacrine-based CDK9 inhibitors with nanomolar inhibitory potency against CDK9, good selectivity over CDK2, and weaker acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition. Among these, compound ZLWT-48 possessed promising antiproliferative activity (GI₅₀ = 0.889 μM for HCT116), potent CDK9 inhibition (IC₅₀ = 8.639 nM), and excellent selectivity over CDK2 (IC₅₀ > 500 nM, Selectivity Index > 57). In addition, ZLWT-48 exhibited lower inhibitory activity against AChE and BuChE compared to the parent compound tacrine. The in vitro studies demonstrated that ZLWT-48 could significantly inhibit cell proliferation, induce apoptosis, suppress migration, and block invasion in HCT116 cells. These findings indicated that compound ZLWT-48 was a potential lead compound as a CDK9 inhibitor that deserves further structural modification for the treatment of cancer.