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是一款口服活性的组蛋白去乙酰化酶（histone deacetylases, HDACs）抑制剂，目前正针对多发性骨髓瘤、白血病与淋巴瘤开展临床试验。该化合物的氢键供体与受体数量极少，但属于手性2-芳基丁酸酯类化合物，存在潜在的消旋化风险。本研究报道了一类带有环烷基基团的非手性AR-42类似物，该基团通过季碳原子连接；此类类似物对人类I类HDACs的抑制效力最高提升40倍（例如JT86，其针对HDAC1的半最大抑制浓度（IC50）为0.7 nM），对5种人类癌细胞系的细胞毒性最高提升25倍，而在正常人类细胞中的毒性则最高降低70倍。在MM96L黑色素瘤细胞中，JT86促进乙酰化组蛋白H4积累的效力是racAR-42的9倍。分子建模与构效关系研究证实，JT86可结合HDAC1，其中四氢吡喃结构可作为酶表面的疏水屏障，隔绝水分子。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、炎症性疾病）中发挥治疗益处。