Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models.,Journal of Medicinal Chemistry

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Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-20 , DOI: 10.1021/acs.jmedchem.0c00567
Satish Noonepalle ₁ , Sida Shen ₂ , Jakub Ptáček ₃ , Maurício T Tavares ₂ , Guiping Zhang ₂ , Jan Stránský ₄ , Jiří Pavlíček ₄ , Glaucio M Ferreira ₅ , Melissa Hadley ₁ , Guido Pelaez ₁ , Cyril Bařinka ₃ , Alan P Kozikowski ₆ , Alejandro Villagra ₁

Affiliation

Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using in silico simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms. In vitro characterization of Suprastat demonstrates subnanomolar HDAC6 inhibitory potency and a hundred- to a thousand-fold HDAC6 selectivity over the other HDAC isoforms. In vivo studies reveal that a combination of Suprastat and anti-PD1 immunotherapy enhances antitumor immune response, mediated by a decrease of protumoral M2 macrophages and increased infiltration of antitumor CD8+ effector and memory T-cells.

中文翻译：

Suprastat的合理设计：黑色素瘤模型中具有增强免疫治疗能力的新型选择性组蛋白脱乙酰基酶6抑制剂。

对组蛋白脱乙酰基酶6（HDAC6）的选择性抑制被认为是治疗癌症的方法。在这项研究中，我们使用计算机模拟设计了一种新的HDAC6抑制剂，名为Suprastat 。X射线晶体学和分子动力学模拟提供了有力的证据来支持这一观点，即Suprastat封端基团中的氨基甲基和羟基与残基D460，N530和S531建立了直接或水介导的显着氢键相互作用，在调节酶的脱乙酰酶功能中起着至关重要的作用，而在其他同工型中则没有。Suprastat的体外表征表明，亚纳摩尔HDAC6抑制能力强，并且HDAC6选择性比其他HDAC同种型高一百至千倍。体内研究表明，Suprastat和抗PD1免疫疗法的组合可增强抗肿瘤免疫反应，介导的是肿瘤前M2巨噬细胞的减少以及抗肿瘤CD8 +效应子和记忆T细胞的浸润增加。

更新日期：2020-09-24

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