化学
细胞毒性
HDAC1型
癌症研究
IC50型
细胞生长
癌细胞
酶
组蛋白脱乙酰基酶
生物化学
立体化学
体外
组蛋白
药理学
癌症
DNA
内科学
生物
医学
作者
Jiahui Tng,Junxian Lim,Kai-Chen Wu,Andrew J. Lucke,Weijun Xu,Robert L. Reid,David P. Fairlie
标识
DOI:10.1021/acs.jmedchem.0c00230
摘要
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.
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