State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China.
Howard Hughes Medical Institute; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
J Med Chem. 2021 Oct 28;64(20):15280-15296. doi: 10.1021/acs.jmedchem.1c01311. Epub 2021 Oct 8.
To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.
为了利用天然产物靛玉红的独特支架，我们在此采用组合药效团的策略，设计并合成了一系列新型靛玉红衍生物，作为细胞周期蛋白依赖性激酶（CDK）和组蛋白去乙酰化酶（HDAC）的双重抑制剂。其中，先导化合物 对 CDK2/4/6 和 HDAC6 的抑制活性较强，IC50 值分别为 60.9 ± 2.9、276 ± 22.3、27.2 ± 4.2 和 128.6 ± 0.4 nM，可有效诱导多种癌细胞系凋亡和 S 期阻滞。特别是化合物 可以通过 Mcl-1/XIAP/PARP 轴来阻止非小细胞肺癌细胞系（A549）的增殖，这与 HDAC 抑制剂和 CDK 抑制剂联合作用的独特模式一致。在 A549 Xerograph 模型中，化合物 表现出与双重抑制相关的显著抗肿瘤疗效。我们的数据表明，化合物 作为一种单一药物，与 CDK 和 HDAC 抑制剂联合使用，可能成为癌症治疗的有前途的候选药物。
