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

New Journal of Chemistry Pub Date: 2022-09-16 DOI: 10.1039/D2NJ03667C

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.

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