Last update 01 Nov 2024

HDAC10

Last update 01 Nov 2024

Basic Info

Synonyms

DKFZP761B039, HD10, HDAC10

+ [2]

Introduction

Polyamine deacetylase (PDAC), which acts preferentially on N(8)-acetylspermidine, and also on acetylcadaverine and acetylputrescine (PubMed:28516954). Exhibits attenuated catalytic activity toward N(1),N(8)-diacetylspermidine and very low activity, if any, toward N(1)-acetylspermidine (PubMed:28516954). Histone deacetylase activity has been observed in vitro (PubMed:11861901, PubMed:11726666, PubMed:11677242, PubMed:11739383). Has also been shown to be involved in MSH2 deacetylation (PubMed:26221039). The physiological relevance of protein/histone deacetylase activity is unclear and could be very weak (PubMed:28516954). May play a role in the promotion of late stages of autophagy, possibly autophagosome-lysosome fusion and/or lysosomal exocytosis in neuroblastoma cells (PubMed:23801752, PubMed:29968769). May play a role in homologous recombination (PubMed:21247901). May promote DNA mismatch repair (PubMed:26221039).

Drugs associated with HDAC10

5e(TES Pharma)

Target

HDAC1 x HDAC10 x HDAC2 x HDAC3 x HDAC6 x HDAC8

Mechanism

HDAC1 modulators [+5]

Active Org.

Fudan University

Originator Org.

TES Pharma SRL

Active Indication

Ovarian Epithelial Carcinoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

TH-34

Target

HDAC10 x HDAC6 x HDAC8

Mechanism

HDAC10 inhibitors [+2]

Active Org.-

Originator Org.-

Active Indication-

Inactive Indication

Neuroblastoma

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

P-1016

Target

HDAC10

Mechanism

HDAC10 modulators

Active Org.-

Originator Org.

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

Active Indication-

Inactive Indication

Neuroblastoma

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with HDAC10

100 Translational Medicine associated with HDAC10

0 Patents (Medical) associated with HDAC10

181

Literatures (Medical) associated with HDAC10

10 Oct 2024·ACS Medicinal Chemistry Letters

Design, Synthesis, and Structural Evaluation of Acetylated Phenylthioketone Inhibitors of HDAC10

Article

Author: Christianson, David W. ; Goulart Stollmaier, Juana ; Watson, Paris R.

Histone deacetylase 10 (HDAC10) is unique among the greater HDAC family due to its unusually narrow substrate specificity as a polyamine deacetylase, specifically as an N ⁸-acetylspermidine hydrolase. Polyamines are essential for cell growth and proliferation; consequently, inhibition of polyamine deacetylation represents a possible strategy for cancer chemotherapy. In this work, we have designed six acetylated phenylthioketone inhibitors of HDAC10 containing positively charged para- and meta-substituted amino groups designed to target interactions with E274, the gatekeeper that recognizes the positively charged ammonium group of the substrate N ⁸-acetylspermidine. We prepared each of these inhibitors through a short synthetic route of six steps. By adapting a low-cost colorimetric activity assay, we measured low-micromolar IC₅₀ values for these compounds against a humanized construct of zebrafish HDAC10 (A24E-D94A HDAC10). Selected inhibitors were cocrystallized with A24E-D94A zebrafish HDAC10 and zebrafish HDAC6 to provide insight into class IIb isozyme affinity and selectivity.

01 Oct 2024·Transplantation

Differential Effects of HDAC6 Inhibition Versus Knockout During Hepatic Ischemia–Reperfusion Injury Highlight Importance of HDAC6 C-terminal Zinc-finger Ubiquitin-binding Domain

Article

Author: Hancock, Wayne W. ; Kurz, Thomas ; Levine, Matthew H. ; DePaolo, John ; Krumeich, Lauren ; O’Brien, Ciaran ; Hernandez, Paul T. ; Murken, Douglas R. ; Beier, Ulf H. ; Concors, Seth J. ; Ge, Guanghui ; Kozikowski, Alan P. ; Aufhauser, David D. ; Wang, Zhonglin ; Avelar, Leandro A. Alves ; Xiong, Yan ; Bhatti, Tricia R.

Background.Ischemia–reperfusion injury (IRI) causes significant morbidity in liver transplantation among other medical conditions. IRI following liver transplantation contributes to poor outcomes and early graft loss. Histone/protein deacetylases (HDACs) regulate diverse cellular processes, play a role in mediating tissue responses to IRI, and may represent a novel therapeutic target in preventing IRI in liver transplantation.Methods.Using a previously described standardized model of murine liver warm IRI, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were assessed at 24 and 48 h after reperfusion to determine the effect of different HDAC inhibitors.Results.Broad HDAC inhibition with trichostatin-A (TSA) was protective against hepatocellular damage (P < 0.01 for AST and P < 0.05 for ALT). Although HDAC class I inhibition with MS-275 provided statistically insignificant benefit, tubastatin-A (TubA), an HDAC6 inhibitor with additional activity against HDAC10, provided significant protection against liver IRI (P < 0.01 for AST and P < 0.001 for ALT). Surprisingly genetic deletion of HDAC6 or -10 did not replicate the protective effects of HDAC6 inhibition with TubA, whereas treatment with an HDAC6 BUZ-domain inhibitor, LakZnFD, eliminated the protective effect of TubA treatment in liver ischemia (P < 0.01 for AST and P < 0.01 for ALT).Conclusions.Our findings suggest TubA, a class IIb HDAC inhibitor, can mitigate hepatic IRI in a manner distinct from previously described class I HDAC inhibition and requires the HDAC6 BUZ-domain activity. Our data corroborate previous findings that HDAC targets for therapeutic intervention of IRI may be tissue-specific, and identify HDAC6 inhibition as a possible target in the treatment of liver IRI.

01 Oct 2024·European Journal of Medicinal Chemistry

Design, synthesis, and evaluation of antitumor activity of 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives as PD-1/PD-l1 inhibitors

Article

Author: Plewka, Jacek ; Zhou, Shijia ; Zhang, Hua ; Wu, Yanling ; Wang, Ming ; Awadasseid, Annoor ; Magiera-Mularz, Katarzyna ; Sun, Shishi ; Zhang, Wen ; Zhu, Mengyu ; Yu, Qimeng ; Wu, Caiyun ; Zhang, Feng

A series of novel 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives was designed, synthesized, and evaluated for their antitumor effects as PD-1/PD-L1 inhibitors both in vitro and in vivo. Firstly, the ability of these compounds to block the PD-1/PD-L1 immune checkpoint was assessed using the homogeneous time-resolved fluorescence (HTRF) assay. Two of the compounds can strongly block the PD-1/PD-L1 interaction, with IC₅₀ values of less than 10 nM, notably, compound HD10 exhibited significant clinical potential by inhibiting the PD-1/PD-L1 interaction with an IC₅₀ value of 3.1 nM. Further microscale thermophoresis (MST) analysis demonstrated that HD10 had strong interaction with PD-L1 protein. Co-crystal structure (2.7 Å) analysis of HD10 in complex with the PD-L1 protein revealed a strong affinity between the compound and the target PD-L1 dimer. This provides a solid theoretical basis for further in vitro and in vivo studies. Next, a typical cell-based experiment demonstrated that HD10 could remarkably prevent the interaction of hPD-1 293 T cells from human recombinant PD-L1 protein, effectively restoring T cell function, and promoting IFN-γ secretion in a dose-dependent manner. Moreover, HD10 was effective in suppressing tumor growth (TGI = 57.31 %) in a PD-1/PD-L1 humanized mouse model without obvious toxicity. Flow cytometry, qPCR, and immunohistochemistry data suggested that HD10 inhibits tumor growth by activating the immune system in vivo. Based on these results, it seems likely that HD10 is a promising clinical candidate that should be further investigated.

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HDAC10

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