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.