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1.
RNA ; 23(4): 567-577, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28096517

RESUMO

Nonsense mutations resulting in a premature stop codon in an open reading frame occur in critical tumor suppressor genes in a large number of the most common forms of cancers and are known to cause or contribute to the progression of disease. Low molecular weight compounds that induce readthrough of nonsense mutations offer a new means of treating patients with genetic disorders or cancers resulting from nonsense mutations. We have identified the nucleoside analog clitocine as a potent and efficacious suppressor of nonsense mutations. We determined that incorporation of clitocine into RNA during transcription is a prerequisite for its readthrough activity; the presence of clitocine in the third position of a premature stop codon directly induces readthrough. We demonstrate that clitocine can induce the production of p53 protein in cells harboring p53 nonsense-mutated alleles. In these cells, clitocine restored production of full-length and functional p53 as evidenced by induced transcriptional activation of downstream p53 target genes, progression of cells into apoptosis, and impeded growth of nonsense-containing human ovarian cancer tumors in xenograft tumor models. Thus, clitocine induces readthrough of nonsense mutations by a previously undescribed mechanism and represents a novel therapeutic modality to treat cancers and genetic diseases caused by nonsense mutations.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Códon sem Sentido/efeitos dos fármacos , Furanos/farmacologia , Nucleosídeos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Nucleosídeos de Pirimidina/farmacologia , Proteína Supressora de Tumor p53/agonistas , Animais , Antimetabólitos Antineoplásicos/síntese química , Antimetabólitos Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/metabolismo , Linhagem Celular Tumoral , Feminino , Furanos/síntese química , Furanos/metabolismo , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Nus , Nucleosídeos/síntese química , Nucleosídeos/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Biossíntese de Proteínas , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/metabolismo , Transdução de Sinais , Ativação Transcricional , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Bioorg Med Chem Lett ; 23(13): 3947-53, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23683597

RESUMO

A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides was prepared and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compounds with low nanomolar potency against the HCV genotype 1b replicon. Among these, compound 8c has identified as a potent HCV replicon inhibitor (EC50=4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compound 8c had a good pharmacokinetic profile in rats with an IV half-life of 6h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compounds. These compounds hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Indóis/farmacologia , Piridinas/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/administração & dosagem , Antivirais/química , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Hepacivirus/genética , Humanos , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/genética
3.
Bioorg Med Chem Lett ; 23(13): 3942-6, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23683596

RESUMO

A series of novel 2-phenylindole analogs were synthesized and evaluated for activity in subgenomic HCV replicon inhibition assays. Several compounds containing small alkyl sulfonamides on the phenyl ring exhibiting submicromolar EC50 values against the genotype 1b replicon were identified. Among these, compound 25d potently inhibited the 1b replicon (EC50=0.17 µM) with 147-fold selectivity with respect to cytotoxicity. Compound 25d was stable in the presence of human liver microsomes and had a good pharmacokinetic profile in rats with an IV half-life of 4.3h and oral bioavailability (F) of 58%.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Indóis/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Sulfonamidas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/administração & dosagem , Antivirais/química , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
4.
Nature ; 447(7140): 87-91, 2007 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-17450125

RESUMO

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.


Assuntos
Códon sem Sentido/genética , Doenças Genéticas Inatas/tratamento farmacológico , Doenças Genéticas Inatas/genética , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Biossíntese de Proteínas/efeitos dos fármacos , Alelos , Animais , Disponibilidade Biológica , Distrofina/biossíntese , Distrofina/genética , Doenças Genéticas Inatas/sangue , Humanos , Camundongos , Camundongos Endogâmicos mdx , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacocinética , Fenótipo , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Especificidade por Substrato
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