RESUMO
BACKGROUND: The IGF-1 receptor (IGF-1R) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies. Therefore, this receptor has become a major focus for the development of anticancer agents. RESULTS: Our lead optimization efforts that blended structure-based design and empirical medicinal chemistry led to the discovery of OSI-906, a novel small-molecule dual IGF-1R/insulin receptor (IR) kinase inhibitor. OSI-906 potently and selectively inhibits autophosphorylation of both human IGF-1R and IR, displays in vitro antiproliferative effects in a variety of tumor cell lines and shows robust in vivo anti-tumor efficacy in an IGF-1R-driven xenograft model when administered orally once daily. CONCLUSION: OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable preclinical drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clinical testing.
Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazinas/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular , Feminino , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/metabolismo , Camundongos , Camundongos Nus , Microssomos/metabolismo , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Pirazinas/síntese química , Pirazinas/química , Pirazinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/química , Receptor de Insulina/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The binding of FtsZ to ZipA is a potential target for antibacterial therapy. Based on a small molecule inhibitor of the ZipA-FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding. The X-ray crystal structure of one of these molecules complexed with ZipA was solved. The structure revealed an unexpected binding mode, facilitated by desolvation of a loosely bound surface water.