RESUMO
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.
Assuntos
Antineoplásicos/farmacocinética , Inibidores Enzimáticos/farmacocinética , Inibidores de Histona Desacetilases , Organofosfonatos/farmacocinética , Proteínas Repressoras/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona Desacetilase 1 , Histona Desacetilase 2 , Histona Desacetilases/metabolismo , Camundongos , Camundongos Nus , Organofosfonatos/síntese química , Organofosfonatos/química , Proteínas Repressoras/metabolismo , Transplante HeterólogoRESUMO
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.
Assuntos
Inibidores de Histona Desacetilases , Animais , Técnicas de Química Combinatória , Cães , Desenho de Fármacos , Histona Desacetilase 1 , Histona Desacetilase 2 , Humanos , Estrutura Molecular , Ratos , Proteínas Repressoras/antagonistas & inibidores , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Glicina/análogos & derivados , Inibidores de Histona Desacetilases , Fenilalanina/química , Acetilação , Amidas , Animais , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Cães , Canal de Potássio ERG1 , Inibidores Enzimáticos/farmacocinética , Canais de Potássio Éter-A-Go-Go/metabolismo , Glicina/química , Histona Desacetilase 1 , Humanos , Macaca mulatta , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
