An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection

Abstract

Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-molecule inhibitors. Here, we report the synthesis of a series of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clinically experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chemically matched inhibitors to probe the role of class I HDACs in β-cell pathobiology and demonstrate for the first time that selective inhibition of an individual HDAC isoform retains beneficial biological activity and mitigates mechanism-based toxicities. The highly selective HDAC3 inhibitor BRD3308 suppressed pancreatic β-cell apoptosis induced by inflammatory cytokines, as expected, or now glucolipotoxic stress, and increased functional insulin release. In addition, BRD3308 had no effect on human megakaryocyte differentiation, while inhibitors of HDAC1 and 2 were toxic. Our findings demonstrate that the selective inhibition of HDAC3 represents a potential path forward as a therapy to protect pancreatic β-cells from inflammatory cytokines and nutrient overload in diabetes.

Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion

“…It has been shown previously that pharmacological HDAC3 inhibition or knockdown in cell culture can maintain glucose-stimulated insulin secretion in the presence of cytokines [8], [10], [12]. Of note, HDAC3βKO mice on normal chow displayed significantly increased circulating insulin after a 16 h fast, as well as 3 min after a glucose challenge (Figure 4A).…”

“…Class I HDACs are ubiquitously expressed and have been implicated in regulation of metabolic gene signatures [7]. In the past several years, multiple studies of siRNA knockdown and pharmacological inhibition of HDAC3 have suggested a role for HDAC3 in β-cells, with loss of HDAC3 function protecting β-cells from cytokine-induced apoptosis and helping to maintain proper glucose-stimulated insulin secretion [8], [9], [10], [11], [12]. Furthermore, an HDAC3-specific inhibitor was reported to improve glucose homeostasis and insulin secretion in a diabetic rat model [11].…”

CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas

“…S14A and 14B). Notably, treatment of CREBBP knockdown cells with a selective HDAC3 inhibitor (22) rescued the expression of most of these MHC class II genes (Figure 5A and 5B), H3K27ac enrichment at their enhancers (Figure 5C and 5D), and restored expression of cell surface HLA-DR (Figure 5E to 5H, and Supplementary Fig. S14A and 14B).…”

Comparison of the Deacylase and Deacetylase Activity of Zinc-Dependent HDACs

“…Additionally, a recent publication also reported on fluorination-based HDAC3 selectivity. 31 As such, we utilized both of these findings by incorporation of a fluorine to 1f , which resulted in compound 2 . This inhibitor possessed 15-fold selectivity for HDAC3 compared to HDAC1 (Figure 5b) while also increasing its inhibitory potency further toward HDAC3.…”