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

Abstract

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 IC 50 = 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.

Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

“… 44 Several studies have reported that I3MO efficiently induces malignant cell apoptosis, inhibits cyclin-dependent kinases, and triggers anti-angiogenesis effects in hematologic malignancies and solid tumors. 45 , 46 , 47 In the current report, the in vitro and in vivo study demonstrated the promising therapeutic role of I3MO on inhibiting of MM cell growth, even in the presence of the protective tumor associated microenvironment (TAM). Of note, combination of I3MO with bortezomib notably enhanced MM cell sensitivity to bortezomib-induced apoptosis.…”

Attenuation of NLRP3 Inflammasome Activation by Indirubin-Derived PROTAC Targeting HDAC6

“…In our previous study, we developed a series of CDK/HDAC dual inhibitors by decorating a natural product, indirubin, which has a unique scaffold of bisindole and is the major active ingredient of Danggui Longhui Wan , a traditional Chinese prescription used to treat chronic myelogenous leukemia (CML). , Further study has shown that the modification of bisindole of indirubins can interfere the ATP-binding and thus abolish the inhibitory activity against CDK, while the installation of 3′-substituted group of indirubins with a linker and a zinc binding group (ZBG) leads to potent and selective inhibition of HDAC6 (Table S1). Therefore, we reason that a CDK/HDAC6 inhibitor ( 8b ) from our previous study should be easily transformed to HDAC6 PROTACs by introducing pomalidomide for the recruitment of CRBN with a linker at the 1-position of 8b (Figure B).…”

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

“…The dual CDK/tyrosine kinase A (TRKA) inhibitor PHA-848125 has demonstrated good antitumor activity in many preclinical tumor models . A series of dual inhibitors of CDK and histone deacetylase (HDAC) have been synthesized based on the unique scaffold of the natural product indirubin . The preclinical results from these compounds corroborate the safety and efficacy observed in preclinical studies and support further clinical evaluation.…”