ABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Imidazoles/therapeutic use , Neoplasms/drug therapy , Pyrazines/therapeutic use , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Line , Female , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/metabolism , Mice , Mice, Nude , Microsomes/metabolism , Models, Molecular , Molecular Structure , Protein Conformation , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrazines/metabolism , Rats , Rats, Sprague-Dawley , Receptor, IGF Type 1/chemistry , Receptor, Insulin/chemistry , Xenograft Model Antitumor AssaysABSTRACT
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.
