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

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Novel tacrine derivatives as potential CDK9 inhibitors with low cholinesterase inhibitory properties: design, synthesis, and biological evaluation
New Journal of Chemistry ( IF 2.7 ) Pub Date : 2022-09-16 , DOI: 10.1039/d2nj03667c
Wenwu Liu _{1,

2} , Yaoguang Huang ₂ , Limeng Wu ₂ , Wenjie Liu ₂ , Xiaowen Jiang ₂ , Zihua Xu _{1,

3} , Qingchun Zhao _{1,

2}

Affiliation

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.

中文翻译：

新型他克林衍生物作为具有低胆碱酯酶抑制特性的潜在 CDK9 抑制剂：设计、合成和生物学评价

细胞周期蛋白依赖性激酶 9 (CDK9) 已被确定为治疗癌症的重要药物靶点。在这里，我们报告了一系列基于他克林的 CDK9 抑制剂的发现，这些抑制剂对 CDK9 具有纳摩尔抑制效力，对 CDK2 具有良好的选择性，并且对乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BuChE) 的抑制作用较弱。其中，化合物ZLWT-48具有良好的抗增殖活性（HCT116 的 GI ₅₀ = 0.889 μM）、有效的 CDK9 抑制作用（IC ₅₀ = 8.639 nM）和优于 CDK2 的优异选择性（IC ₅₀ > 500 nM，选择性指数 > 57）。此外，与母体化合物他克林相比， ZLWT-48对 AChE 和 BuChE 的抑制活性较低。这体外研究表明，ZLWT-48可显着抑制 HCT116 细胞的增殖、诱导凋亡、抑制迁移和阻断侵袭。这些发现表明，化合物ZLWT-48是一种潜在的先导化合物，可作为 CDK9 抑制剂，值得进一步进行结构修饰以治疗癌症。

更新日期：2022-09-16

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