Product Name: OSI-906(Linsitinib)
 CAT#: A-1058

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  Synonym:OSI906,Linsitinib

OSI-906 Chemical Structure
OSI-906 chemical structure


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IUPAC/Chemical name: (1r,3r)-3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

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Biological Activity

OSI-906 is a potent, selective orally active inhibitor of the insulin-like growth factor-1 receptor (IGF-1R). IGF-1R has been viewed as an important therapeutic target due to its involvement in the growth and proliferation in a variety of human cancers, including adrenocortical carcinoma (ACC), ovarian and non-small cell lung cancers. A major challenge in the development of IGF-1R inhibitors is to avoid blocking the closely related insulin receptor that regulates glucose levels in the blood. OSI-906 is currently in Phase III clinical trials in ACC and in Phase I/II clinical trials in ovarian cancer.

Technical Data

Formula:C26H23N5O
M.Wt: 421.49
CAS #:867160-71-2
Cis-isomer :100% by NMR
Chemical Purity:>99% by HPLC
Storage Conditions :Room temperature, or -20ºC for 2 year.
OSI-906 MSDS OSI-906 CoA

Reference
Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor.
Future Med Chem. 2009 Sep;1(6):1153-71. doi: 10.4155/fmc.09.89.
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.

Linsitinib (OSI-906) was developed through drug-discovery efforts focused on identifying a potent and selective, small-molecule inhibitor of the IGF-1R signaling axis. The lead optimization phase utilized IR and IGF-1R co-crystal structures, with lead compounds from the imidazopyrazine series, to afford a structure-based design-driven component, which complemented ongoing empirical medicinal chemistry efforts. These combined approaches improved metabolic and pharmacokinetic liabilities of earlier lead compounds and ultimately led to the discovery of OSI-906. OSI-906 was synthesized from an advanced imidazopyrazine intermediate in two linear steps. OSI-906 potently inhibits ligand-dependent auto-phosphorylation of both human IGF-1R and IR in cells, while displaying a high degree of selectivity versus a wide panel of protein kinases. Moreover, OSI-906, through its inhibition of both IGF-1R and IR, prevents ligand-induced activation of downstream pathways including pAKT, pERK1/2 and p-p70S6K and, therefore, inhibits proliferation in a variety of tumor cell lines. Robust anti-tumor activity was achieved in an IGF-1R-driven LISN xenograft model following once-daily oral administration of OSI-906. The anti-tumor activity obtained in this study correlated well with the degree and duration of inhibition of tumor IGF-1R phosphorylation achieved in vivo by OSI-906. OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with demonstrated in vivo efficacy in tumor models. It is currently being evaluated in clinical trials. Furthermore, the exceptional selectivity profile of OSI-906 in conjunction with its ability to inhibit both IGF-1R and IR provides the unique opportunity to fully target the IGF-1R/IR axis. (source: Future Medicinal Chemistry September 2009, Vol. 1, No. 6, Pages 1153-1171. )


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