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1.
ACS Chem Neurosci ; 7(2): 240-58, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26599234

RESUMO

Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A.


Assuntos
Doença de Charcot-Marie-Tooth/tratamento farmacológico , Doença de Charcot-Marie-Tooth/enzimologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Acetilação/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Células Cultivadas , Modelos Animais de Doenças , Gânglios Espinais/citologia , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Humanos , Interleucina-2/genética , Camundongos , Camundongos Transgênicos , Mutação/genética , Neuroblastoma/patologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
2.
Alzheimers Res Ther ; 6(1): 12, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24576665

RESUMO

INTRODUCTION: Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. METHODS: We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). RESULTS: We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically. CONCLUSION: Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology.

3.
J Med Chem ; 56(16): 6297-313, 2013 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-23627282

RESUMO

This Perspective provides an in depth look at the numerous disease states in which histone deacetylase 6 (HDAC6) has been implicated. The physiological pathways, protein-protein interactions, and non-histone substrates relating to different pathological conditions are discussed with regard to HDAC6. Furthermore, the compounds and methods used to modulate HDAC6 activity are profiled. The latter half of this Perspective analyzes reported HDAC6 selective inhibitors in terms of structure, potency, and selectivity over the other HDAC isoforms with the intent of providing a comprehensive overview of the molecular tools available. Potential obstacles and future directions of HDAC6 research are also presented.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Doença/classificação , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/uso terapêutico , Humanos
4.
J Med Chem ; 55(22): 9891-9, 2012 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-23009203

RESUMO

The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5 g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ∼600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Ácidos Hidroxâmicos/farmacologia , Melanoma Experimental/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Ureia/química , Acetilação , Animais , Antineoplásicos/síntese química , Western Blotting , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/síntese química , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Isoenzimas , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos , Estrutura Molecular , Compostos de Fenilureia/síntese química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
5.
ACS Med Chem Lett ; 3(1): 15-19, 2012 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-22754607

RESUMO

We report the design and synthesis of novel FTPA-triazole compounds as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt), through a focus on thioether and isoprenoid mimetics. These mimetics were coupled utilizing a copper-assisted cycloaddition to assemble the potential inhibitors. Using the resulting triazole from the coupling as an isoprenyl mimetic resulted in the biphenyl substituted FTPA triazole 10n. This lipid-modified analog is a potent inhibitor of Icmt (IC(50) = 0.8 ± 0.1 µM; calculated K(i) = 0.4 µM).

6.
Bioorg Med Chem Lett ; 21(18): 5616-9, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21782433

RESUMO

Inhibition of isoprenylcysteine carboxyl methyltransferase (Icmt) offers a promising strategy for K-Ras driven cancers. We describe the synthesis and inhibitory activity of substrate-based analogs derived from several novel scaffolds. Modifications of both the prenyl group and thioether of N-acetyl-S-farnesyl-L-cysteine (AFC), a substrate for human Icmt (hIcmt), have resulted in low micromolar inhibitors of Icmt and have given insights into the nature of the prenyl binding site of hIcmt.


Assuntos
Cisteína/análogos & derivados , Inibidores Enzimáticos/farmacologia , Lipídeos/química , Proteínas Metiltransferases/antagonistas & inibidores , Enxofre/química , Cisteína/síntese química , Cisteína/química , Cisteína/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Proteínas Metiltransferases/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
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