Second-Generation Histone Deacetylase 6 Inhibitors Enhance the Immunosuppressive Effects of Foxp3+ T-Regulatory Cells

Abstract

Second-generation Tubastatin A analogues were synthesized and evaluated for their ability to inhibit selectively histone deacetylase 6 (HDAC6). Substitutions to the carboline cap group were well-tolerated with substitution at the 2-position of both β- and γ-carbolines being optimal for HDAC6 activity and selectivity. Some compounds in this series were determined to have subnanomolar activity at HDAC6 with more than 7000 fold selectivity for HDAC6 versus HDAC1. Selected compounds were then evaluated for their ability to augment the immunosuppressive effect of Foxp3+ regulatory T cells. All compounds tested were found to enhance the ability of regulatory T cells to inhibit the mitotic division of effector T cells both in vitro and in vivo, suggesting that further investigation into the use of these compounds for the treatment of autoimmune disorders is warranted.

Targeting Selective Autophagy of Insoluble Protein Aggregates

“…Its selectivity vs. HDAC1 is an unprecedented ≈5000, and its ADMET profile is further improved compared to tubastatin. The efficacy of 5.38b in cellular assays related to Tregs-dependent suppression of T cell-dependent immune responses is similar to tubastatin [156]. The sulfone analogue of tubastatin (tubathian A, 5.39) is as potent and selective in vitro as its parent compound, and may represent another structural avenue for further optimization of HDAC6-selective inhibitors [157].…”

“…The tubastatin analogue 5.38b bearing a 2-methylamido substituent is the result of a structural optimization program [156]. Its selectivity vs. HDAC1 is an unprecedented ≈5000, and its ADMET profile is further improved compared to tubastatin.…”

Embryonic Life of Hdac Inhibitors: – In Diabetic Nephropathy

“…[24,25] HDACIs also have effects on non-histone proteins which include proteins involved in the regulation of gene expression, pathways of extrinsic and intrinsic apoptosis, cell-cycle progression, redox pathways, mitotic division, DNA repair, cell migration and angiogenesis. [2,[33][34][35][36][37][38][39] In general, amplified levels of histone acetylation lead to de-condensation of chromatin allowing DNA accessible to transcription factors, and are thus related with increased transcriptional activity, whereas decreased acetylation levels are associated with transcriptional repression. [23] A recent study, however, verified that structurally different HDAC inhibitors significantly activated or repressed more than 40% of genes on the array in cultured acute T-cell leukemia cell line.…”

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

“…Subsequently, a highly selective HDAC6 inhibitor, compound 13, possessing a phenyl linking motif and a chiral capping moiety was reported in 2009 by Smil et al [59] The alternative phenyl linking motif takes advantage of the wider and shallower channel topology of HDAC6, while the cap group forms favorable surface interactions (IC 50 =0.010 μM) and confers HDAC6 selectivity (>40-fold vs all HDACs). An alternatively-capped, phenyllinked HDAC6-selective inhibitor, tubastatin A (15 nM, >57-fold vs all HDACs), was described by Butler et al in 2010 [60], and subsequent analogs with improved potency and selectivity were later reported [61]. In an effort to identify novel, selective, and highly efficient HDAC6 inhibitors, Wagner et al [62] reported a linker-based strategy exploiting close contacts and structural differences between the various isoforms within the catalytic binding domain of HDAC6.…”