更新于：2024-11-01

HDAC10

更新于：2024-11-01

基本信息

别名

DKFZP761B039、HD10、HDAC10

+ [2]

简介

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).

关联

项与 HDAC10 相关的药物

5e(TES Pharma)

靶点

HDAC1 x HDAC10 x HDAC2 x HDAC3 x HDAC6 x HDAC8

作用机制

HDAC1 modulators [+5]

在研机构

复旦大学

原研机构

TES Pharma SRL

在研适应症

卵巢上皮癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

TH-34

靶点

HDAC10 x HDAC6 x HDAC8

作用机制

HDAC10抑制剂 [+2]

在研机构-

原研机构-

在研适应症-

非在研适应症

神经母细胞瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

P-1016

靶点

HDAC10

作用机制

HDAC10 modulators

在研机构-

原研机构

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

在研适应症-

非在研适应症

神经母细胞瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 HDAC10 相关的临床结果

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100 项与 HDAC10 相关的转化医学

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0 项与 HDAC10 相关的专利（医药）

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181

项与 HDAC10 相关的文献（医药）

2024-10-10·ACS Medicinal Chemistry Letters

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

Article

作者: 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.

2024-10-01·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

作者: 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.

2024-10-01·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

作者: 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.

项与 HDAC10 相关的新闻（医药）

2024-05-30

·精准药物

药物筛选中心（暨南大学）对外提供新药筛选服务

咨询合作药物筛选中心（暨南大学），隶属于暨南大学药学院公共科研平台。中心拥有Echo550微量液体超声转移工作站等先进的自动化药物筛选仪器，前期支撑的多个激酶抑制剂已经产业转化及发表JMC等高水平论文。目前，筛选中心建有激酶、蛋白酶、HDAC、COX、GPCR、报告基因、病毒、细菌等筛选模型，能够开展肿瘤、神经系统疾病、心脑血管病、糖尿病、病毒和细菌感染性疾病等领域相关靶标、细胞、机制的筛选和研究，每天能够完成数万次的新药筛选反应。已建立的药物筛选模型1）蛋白水平：激酶：Abl, ABL(M351T), ABL(H396P), ABL(Y253F), ABL1 (E255K), ABL1 (G250E), ABL(Q252H), AKT1, AKT2, AKT3, ALK, ALK5, AuroraA, AuroraB, AXL, BRAF, BRAF(V599E), BTK, DDR1, DDR2, EGFR, EGFR (T790M), EGFR(L858R), EGFR(L861Q), EGFR(T790ML858R), EGFR(D746-750), EGFR(D746-750/T790M), Flt3, FLT3(D835Y), FGFR1, FGFR2, FGFR3, FGFR4, Her2, Her4, KIT, MET, IGF-1R, FGFR1, JAK1, JAK2, JAK3, MAPK10, MAPK14, mTOR, TrkA, TrkB, TrkC,TYK2, KDR, SRC, PDGFRa, PDGFRA(D842V), PDGFRb, RET, ZAK。蛋白酶：MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, MMP-14, ADAM5, ADAM10, ADAMTS13, TACE/ADAM17, Furin, Cathepsin E, Cathepsin D, BACE-1, DDP4, DDP8, DDP9, HIV protease-1, PMVII，PMVIV。HDACs：HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, Sirt1, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6。2）肿瘤细胞活性：近500种肿瘤细胞系；基于Ba/F3的耐药模型3）抗病毒/菌药物筛选：EV71和HSV病毒活性筛选模型；金黄色葡萄球菌、大肠杆菌和沙门氏杆菌等4）体内药效：移植瘤模型对外服务1）体外活性筛选（单剂量抑制率；多剂量IC50）；2）体内药效；3）机制研究；4）药代动力学研究；5）化合物工艺优化、大量订制。咨询合作

临床1期