Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase Inhibitors by Multimodality Molecular Imaging in Living Subjects

Abstract

Histone deacetylases (HDAC) that regulate gene expression are being explored as cancer therapeutic targets. In this study, we focused on HDAC6 based on its ability to inhibit cancerous Hsp90 chaperone activities by disrupting Hsp90/p23 interactions. To identify novel HDAC6 inhibitors, we used a dual-luciferase reporter system in cell culture and living mice by bioluminescence imaging (BLI). On the basis of existing knowledge, a library of hydrazone compounds was generated for screening by coupling cinnamic hydroxamates with aldehydes and ketones. Potency and selectivity were determined by in vitro HDAC profiling assays, with further evaluation to inhibit Hsp90(α/β)/p23 interactions by BLI. In this manner, we identified compound 1A12 as a dose-dependent inhibitor of Hsp90(α/β)/p23 interactions, UKE-1 myeloid cell proliferation, p21waf1 upregulation, and acetylated histone H3 levels. 1A12 was efficacious in tumor xenografts expressing Hsp90(α)/p23 reporters relative to carrier control–treated mice as determined by BLI. Small animal 18F-FDG PET/CT imaging on the same cohort showed that 1A12 also inhibited glucose metabolism relative to control subjects. Ex vivo analyses of tumor lysates showed that 1A12 administration upregulated acetylated-H3 by approximately 3.5-fold. Taken together, our results describe the discovery and initial preclinical validation of a novel selective HDAC inhibitor.

Thiazolidinedione “Magic Bullets” Simultaneously Targeting PPARγ and HDACs: Design, Synthesis, and Investigations of their In Vitro and In Vivo Antitumor Effects

“…Similarly, vorinostat was used at a concentration of 150 mg/kg in urothelial carcinoma . Several other newer HDAC inhibitors have also been evaluated in vivo in various cancer models. − In the case of in vivo evaluation of PPARγ agonists in various cancer models, a similar trend is observed. − Hence, dual-targeting compound 7c with %TGI of 24% appears more potent than single-targeted agents. Considering its in vivo efficacy at higher doses, 7c analogues and other HDAC inhibitors or PPARγ agonists might be used as an adjuvant to existing chemotherapy to help reduce resistance/toxicity issues and possibly enhance antitumor effects in a synergistic manner.…”

The Effects of Guizhi Gancao Decoction on Pressure Overload‐Induced Heart Failure and Posttranslational Modifications of Tubulin in Mice

“…Our data showed that GGD inhibited HDAC6 and increased tubulin acetylation, which may have beneficial effects on heart failure. These effects are consisted with one report that cinnamic acid, one of the major constituents of Cinnamomum cassia Presl., inhibited HDAC activity [ 29 ].…”

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

“…The HDAC inhibitor BAS-2 inhibits HDAC6, affects the ENO1 gene and LDHA related to glucose metabolism, and ultimately affects glycolysis in breast cancer (Dowling et al, 2021). Studies have shown that 1A12 can inhibit the acetylation level of histone H3, and it can also affect the glucose metabolism level in preclinical test subjects (Chan et al, 2014). HDAC inhibitors (panobinostat, vorinostat, and romidepsin) reduce glycolysis in a c-MYC-dependent manner, triggering the metabolic reprogramming of glioblastoma (Nguyen et al, 2020).…”