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1.
Neuro Oncol ; 21(9): 1150-1163, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31111916

RESUMO

BACKGROUND: Medulloblastoma (MB) is one of the most frequent malignant brain tumors of children, and a large set of these tumors is characterized by aberrant activation of the sonic hedgehog (SHH) pathway. While some tumors initially respond to inhibition of the SHH pathway component Smoothened (SMO), tumors ultimately recur due to downstream resistance mechanisms, indicating a need for novel therapeutic options. METHODS: Here we performed a targeted small-molecule screen on a stable, SHH-dependent murine MB cell line (SMB21). Comprehensive isotype profiling of histone deacetylase (HDAC) inhibitors was performed, and effects of HDAC inhibition were evaluated in cell lines both sensitive and resistant to SMO inhibition. Lastly, distinct mouse models of SHH MB were used to demonstrate pharmacologic efficacy in vivo. RESULTS: A subset of the HDAC inhibitors tested significantly inhibit tumor growth of SMB21 cells by preventing SHH pathway activation. Isotype profiling of HDAC inhibitors, together with genetic approaches suggested that concerted inhibition of multiple class I HDACs is necessary to achieve pathway inhibition. Of note, class I HDAC inhibitors were also efficacious in suppressing growth of diverse SMO inhibitor‒resistant clones of SMB21 cells. Finally, we show that the novel HDAC inhibitor quisinostat targets multiple class I HDACs, is well tolerated in mouse models, and robustly inhibits growth of SHH MB cells in vivo as well as in vitro. CONCLUSIONS: Our data provide strong evidence that quisinostat or other class I HDAC inhibitors might be therapeutically useful for patients with SHH MB, including those resistant to SMO inhibition.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Proteínas Hedgehog/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Meduloblastoma/tratamento farmacológico , Anilidas , Animais , Compostos de Bifenilo , Linhagem Celular Tumoral , Neoplasias Cerebelares/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Hedgehog/metabolismo , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Meduloblastoma/metabolismo , Camundongos , Proteínas/genética , Piridinas , Proteínas Repressoras/genética , Transdução de Sinais , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/metabolismo
2.
J Med Chem ; 57(21): 9019-27, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25314271

RESUMO

BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.


Assuntos
Imidazóis/síntese química , Isoxazóis/química , Proteínas Nucleares/antagonistas & inibidores , Pirazinas/síntese química , Fatores de Transcrição/antagonistas & inibidores , Ácidos Alcanossulfônicos/química , Azepinas/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Cristalografia por Raios X , Fluorocarbonos/química , Regulação da Expressão Gênica , Humanos , Imidazóis/farmacologia , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Proteínas Nucleares/química , Pirazinas/farmacologia , Piridinas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade , Fatores de Transcrição/química
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