ABSTRACT
We report the preparation and structure-activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Histone Deacetylase Inhibitors , Organophosphonates/pharmacokinetics , Repressor Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Histone Deacetylase 1 , Histone Deacetylase 2 , Histone Deacetylases/metabolism , Mice , Mice, Nude , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Repressor Proteins/metabolism , Transplantation, HeterologousABSTRACT
The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models.
Subject(s)
Histone Deacetylase Inhibitors , Animals , Combinatorial Chemistry Techniques , Dogs , Drug Design , Histone Deacetylase 1 , Histone Deacetylase 2 , Humans , Molecular Structure , Rats , Repressor Proteins/antagonists & inhibitors , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and improved physical properties. Dose-dependent efficacy in a mouse HCT116 xenograft model was demonstrated with a phenylglycine SHI-1 analog.
Subject(s)
Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Enzyme Inhibitors/pharmacology , Glycine/analogs & derivatives , Histone Deacetylase Inhibitors , Phenylalanine/chemistry , Acetylation , Amides , Animals , Colonic Neoplasms/enzymology , Colonic Neoplasms/pathology , Dogs , ERG1 Potassium Channel , Enzyme Inhibitors/pharmacokinetics , Ether-A-Go-Go Potassium Channels/metabolism , Glycine/chemistry , Histone Deacetylase 1 , Humans , Macaca mulatta , Mice , Molecular Structure , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
