Abstract
A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Benzamides / chemical synthesis
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Benzamides / chemistry
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Benzamides / pharmacology
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Combinatorial Chemistry Techniques
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / drug effects
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Ether-A-Go-Go Potassium Channels / metabolism*
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HCT116 Cells
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Histone Deacetylase Inhibitors*
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Histone Deacetylases
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Histones / analysis
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Humans
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Mice
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Mice, Nude
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Molecular Structure
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Niacinamide / chemical synthesis*
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Niacinamide / chemistry
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Niacinamide / pharmacology*
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Protein Isoforms
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzamides
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Histone Deacetylase Inhibitors
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Histones
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KCNH2 protein, human
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Protein Isoforms
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Spiro Compounds
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Niacinamide
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Histone Deacetylases
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histone deacetylase 3