Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation

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, IC50 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是一种口服活性的组蛋白去乙酰化酶（histone deacetylases, HDACs）抑制剂，目前正处于针对多发性骨髓瘤、白血病与淋巴瘤的临床试验阶段。该化合物的氢键供体与受体数量较少，属于手性2-芳基丁酸酯类物质，且存在潜在的消旋化风险。本研究报道了一类非手性AR-42类似物，其通过季碳原子连接环烷基结构，对人类I类HDACs的抑制活性最高提升40倍（例如JT86，针对HDAC1的半最大抑制浓度（IC50）为0.7 nM）；对五种人类癌细胞系的细胞毒性最高提升25倍，而对正常人类细胞的毒性则最多降低70倍。在MM96L黑色素瘤细胞中，JT86促进乙酰化组蛋白H4积累的活性较外消旋AR-42高9倍。分子建模与构效关系研究证实，JT86可结合HDAC1，其中四氢吡喃环可作为疏水屏障隔绝酶表面的水环境。这类强效I类HDAC抑制剂有望在AR-42已展现活性的疾病（癌症、寄生虫感染、炎症性病症）中发挥治疗益处。