Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation.
Jiahui TngJunxian LimKai-Chen WuAndrew J LuckeWeijun XuRobert C ReidDavid P FairliePublished in: Journal of medicinal chemistry (2020)
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.
Keyphrases
- endothelial cells
- papillary thyroid
- clinical trial
- cell proliferation
- histone deacetylase
- multiple myeloma
- induced pluripotent stem cells
- oxidative stress
- squamous cell
- pluripotent stem cells
- dna methylation
- acute myeloid leukemia
- squamous cell carcinoma
- bone marrow
- photodynamic therapy
- childhood cancer
- molecular dynamics
- randomized controlled trial
- lymph node metastasis
- molecular docking
- anti inflammatory
- open label
- molecular dynamics simulations
- visible light