OSI-906 (Linsitinib) is an orally small-molecule inhibitor of IGF-1R with potential antineoplastic activity. 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 (Linsitinib) selectively inhibits IGF-1R, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis. Overexpressed in a variety of human cancers, IGFR-1 stimulates cell proliferation, enables oncogenic transformation, and suppresses apoptosis. OSI-906 slowed the growth of IGF-1R-dependent tumors, and it also reduced proliferation and/or survival of a broad panel of tumor cell lines.
|Cell lines||NSCLC(H292, H358 and H1703) and CRC(Colo205, HT-29 and RKO) tumor cell lines|
|Preparation method||Cell proliferation assay. cells were seeded into 96-well plates in appropriate media containing FCS 10% and incubated for 3 days in the presence of OSI-906 at various concentrations. Inhibition of cell growth was determined by luminescent quantitation of intracellular ATP content using CellTiterGlo (Promega, Madision , WI, USA). Data were presented as a fraction of maximal proliferation, caculated by dividing the cellular density in the presence of varying concentrations of OSI-906 by the cellular density of control cells treated with vehicle (DMSO) only.|
|Incubation time||72 h|
|Animal models||LISN tumor xenograft model in mice|
|Formulation||25mM tartaric acid|
|Dosages||25mg/kg or 75mg/kg daily for 12 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥84 mg/mL|
|Source||Oncol Rep (2014). Figure 3. OSI-906|
|Cell Lines||GEO cells|
|Incubation Time||48 h|
|Results||Both MK-0646 and OSI-906 treated GEO xenografts had statistically significant increase in apoptosis (p<0.05) as compared with the control tumors|
Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor.
Mulvihill MJ, et al. Future Med Chem. 2009 Sep;1(6):1153-71. PMID: 21425998.
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