Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer.
Cao Z, Yang F, Wang J, Gu Z, Lin S, Wang P, An J, Liu T, Li Y, Li Y, Lin H, Zhao Y, He B.
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 <b>8b</b> with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC<sub>50</sub> = 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 <b>8b</b> 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 <b>8b</b> showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound <b>8b</b> as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.