羟肟酸类 AR-42 的手性衍生物能够强效抑制 I 类组蛋白去乙酰化酶（HDAC）并抑制癌细胞增殖。
Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation.
机构信息
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
出版信息
J Med Chem. 2020 Jun 11;63(11):5956-5971. doi: 10.1021/acs.jmedchem.0c00230. Epub 2020 May 21.
AR-42 is an orally active inhibitor of histone deacetylases (HDACs) in clinical trials for multiple myeloma, leukemia, and lymphoma. It has few hydrogen bond donors and acceptors but is a chiral 2-arylbutyrate and potentially prone to racemization. We report achiral AR-42 analogues incorporating a cycloalkyl group linked via a quaternary carbon atom, with up to 40-fold increased potency against human class I HDACs (e.g., JT86, IC 0.7 nM, HDAC1), 25-fold increased cytotoxicity against five human cancer cell lines, and up to 70-fold less toxicity in normal human cells. JT86 was ninefold more potent than racAR-42 in promoting accumulation of acetylated histone H4 in MM96L melanoma cells. Molecular modeling and structure-activity relationships support binding to HDAC1 with tetrahydropyran acting as a hydrophobic shield from water at the enzyme surface. Such potent inhibitors of class I HDACs may show benefits in diseases (cancers, parasitic infections, inflammatory conditions) where AR-42 is active.
AR-42 是一种组蛋白去乙酰化酶（HDACs）的口服抑制剂，目前正处于多发性骨髓瘤、白血病和淋巴瘤的临床试验阶段。它的氢供体和氢受体较少，但它是一种手性的 2-芳基丁酸，并且可能容易外消旋化。我们报告了一种无手性的 AR-42 类似物，其中包含一个通过季碳原子连接的环烷基，对人类 I 类 HDACs（例如 JT86，IC0.7 nM，HDAC1）的活性提高了 40 倍，对五种人类癌细胞系的细胞毒性提高了 25 倍，对正常人类细胞的毒性降低了 70 倍。JT86 在促进 MM96L 黑色素瘤细胞中乙酰化组蛋白 H4 积累方面比外消旋 AR-42 强 9 倍。分子建模和构效关系支持与 HDAC1 的结合，其中四氢吡喃作为酶表面的疏水屏蔽物，防止与水结合。在 AR-42 有效的疾病（癌症、寄生虫感染、炎症性疾病）中，这种强效的 I 类 HDAC 抑制剂可能会带来益处。
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