Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer

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.