RESUMO
A family of biaryl substituted 1,4-diaminocyclohexanamides of 3-chlorobenzothiophene-2-carboxylic acid is reported as picomolar modulators of Hedgehog protein function. SAR for the 1,4-diaminocyclohexane group is shown to be exquisitely sensitive to substitution on the 4-amino group, and SAR for the 3-chlorobenzothiophene group is highly specific. Preliminary SAR studies of the biaryl substituent led to a picomolar compound with in vivo activity.
Assuntos
Ácidos Carboxílicos/síntese química , Química Farmacêutica/métodos , Proteínas Hedgehog/agonistas , Administração Oral , Animais , Ácidos Carboxílicos/farmacologia , Linhagem Celular , Desenho de Fármacos , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Modelos Biológicos , Modelos Químicos , Acidente Vascular Cerebral/tratamento farmacológico , Relação Estrutura-Atividade , Tiofenos/químicaRESUMO
A small family of phenyl quinazolinone ureas is reported as potent modulators of Hedgehog protein function. Preliminary SAR studies of the urea substituent led to a nanomolar Hedgehog antagonist.
Assuntos
Proteínas Hedgehog/antagonistas & inibidores , Quinazolinonas/síntese química , Animais , Linhagem Celular , Proteínas Hedgehog/fisiologia , Camundongos , Quinazolinonas/química , Quinazolinonas/farmacologia , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
The link between basal cell carcinoma (BCC) and aberrant activation of the Hedgehog (Hh) signaling pathway has been well established in humans and in mouse models. Here we report the development of assays, including two novel in vitro BCC models, which allowed us to screen for Hh inhibitors and test their validity as potential treatments for BCC. We identified a novel small molecule Hh inhibitor (CUR61414) that can block elevated Hh signaling activity resulting from oncogenic mutations in Patched-1. Moreover, CUR61414 can suppress proliferation and induce apoptosis of basaloid nests in the BCC model systems, whereas having no effect on normal skin cells. These findings directly demonstrate that the use of Hh inhibitors could be a valid therapeutic approach for treating BCC.