Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer
Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer
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DOI：
10.1021/acs.jmedchem.1c01311
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发表时间：
2021-10-08
影响因子：
7.3
通讯作者：
He, Bin
中科院分区：
文献类型：
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作者：
Cao, Zhuoxian;Yang, Fenfen;He, Bin
为了利用天然产物靛玉红独特的骨架结构，我们采用组合药效团的策略，设计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，具有显著的CDK 2/4/6和HDAC 6抑制活性的先导化合物8b（IC 50分别为60.9 +/- 2.9、276 +/- 22.3、27.2 +/- 4.2和128.6 +/- 0.4 nM）可以有效地诱导几种癌细胞系的凋亡和S期停滞。特别地，化合物8b可以通过Mcl-1/XIAP/PARP轴防止非小细胞肺癌细胞系（A549）的增殖，这与HDAC抑制剂和CDK抑制剂的组合药剂的独特作用模式一致。在A549静电复印模型中，化合物8b显示出与其双重抑制相关的显著抗肿瘤功效。我们的数据表明，化合物8b作为单一药剂可能是与CDK和HDAC抑制剂组合用于癌症治疗的有希望的候选药物。
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 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 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 8b 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 8b showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound 8b as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.