1. Protein Tyrosine Kinase/RTK
  2. Insulin Receptor
    IGF-1R

Linsitinib (Synonyms: OSI-906)

Cat. No.: HY-10191 Purity: 99.69%
Data Sheet SDS Handling Instructions

Linsitinib is a selective inhibitor of IGF-1R with IC50 of 35 nM, and modestly potent to InsR with IC50 of 75 nM, and has no activity towards Abl, ALK, BTK, EGFR, FGFR1/2, PKA etc.

For research use only. We do not sell to patients.
Linsitinib Chemical Structure

Linsitinib Chemical Structure

CAS No. : 867160-71-2

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Free Sample (0.5-1 mg)   Apply now  
10 mM * 1 mL in DMSO $55 In-stock
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10 mg $70 In-stock
50 mg $155 In-stock
100 mg $215 In-stock
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    Linsitinib purchased from MCE. Usage Cited in: Endocrinology. 2014 Jun;155(6):2102-11.

    OSI-906 inhibits insulin receptor-mediated signaling in HEK293 cells. The cells are deprived of serum for 2 hours, stimulated for 5 min with 1 μM i nsulin in the presence or absence of 200 nM OSI-906 in serum-free medium. Cell extracts are subjected to immunoprecipitation and immunoblotting, as indicated.

    Linsitinib purchased from MCE. Usage Cited in: Okayama University. 2015.

    The role of Semaphorin4D in bone invasion by oral cancer.

    Linsitinib purchased from MCE. Usage Cited in: Sci Rep. 2017 Jun 23;7(1):4119.

    Transient hyperglycemia accompanied by ephemeral hyperinsulinemia induced by IR and IGF1R inhibition with OSI-906. C57BL/6J mice are subjected to a 16-hour fast and OSI-906 (45 mg/kg) or a vehicle (Solutol HS-15) is administered orally 1 hour before injection with either saline, 10 units of insulin, or 1 mg/kg of IGF-1 via the inferior vena cava. The liver and epididymal fat are collected 70 and 120 seconds after injection, respectively. The total protein extracts from the liver and epididymal f
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    Linsitinib is a selective inhibitor of IGF-1R with IC50 of 35 nM, and modestly potent to InsR with IC50 of 75 nM, and has no activity towards Abl, ALK, BTK, EGFR, FGFR1/2, PKA etc.

    IC50 & Target

    IC50: 35 nM (IGF-1R), 75 nM (InsR)

    In Vitro

    Linsitinib inhibits IGF-1R autophosphorylation and activation of the downstream signaling proteins Akt, ERK1/2 and S6 kinase with IC50 of 0.028 to 0.13 μM. Linsitinib enables an intermediate conformation of the target protein through interactions with the C-helix. Linsitinib displays favorable metabolic stability in liver microsomes. Linsitinib fully inhibits both IR and IGF-1R phosphorylation at a concentration of 1 μM. Linsitinib inhibits proliferation of several tumor cell lines including non-small-cell lung cancer and colorectal cancer (CRC) tumor cell line with EC50 of 0.021 to 0.810 μM[1]

    In Vivo

    Linsitinib inhibits tumor growth in an IGF-1R-driven xenograft mouse model, with 100% TGI and 55% regression at a dose of 75 mg/kg and 60% TGI and no regression at a dose of 25 mg/kg. Linsitinib administration induces different elimination half-lives of itself in dog, rat and mice, the elimination half-lives are 1.18 hours, 2.64 hours and 2.14 hours, respectively. Linsitinib administration at different single dose once-daily in femal Sprague-Dawley rat and femal CD-1 mouse reveal that the Vmax is not dose-proportional to Linsitinib dose. Linsitinib elevates the blood glucose levels at a dose of 25 mg/kg after 12 days administration. Linsitinib administration at a single dose of 75 mg/kg in IGF-1R-driven full-length human IGF-1R (LISN) xenograft mouse model achieve maximal inhibition of IGF-1R phosphorylation (80%) between 4 and 24 hours with plasma drug concentrations of 26.6-4.77 μM[1]. Linsitinib administered as a single dose of at 60 mg/kg in NCI-H292 xenografts mice inhibits uptake of glucose at 2, 4, and 24 hours post-treatment in vivo. Linsitinib inhibits the growth of tumors in NCI-H292 xenograft mouse model[2]

    Clinical Trial
    NCT Number Sponsor Condition Start Date Phase
    NCT02546544 University of Oxford|European Organisation for Research and Treatment of Cancer - EORTC|European Commission|Astellas Pharma Inc|Oxford University Hospitals NHS Trust Relapsed Ewing Sarcoma|Refractory Ewing Sarcoma March 2014 Phase 2
    NCT01533246 National Cancer Institute (NCI) Adenocarcinoma of the Prostate|Hormone-resistant Prostate Cancer|Recurrent Prostate Cancer|Stage IV Prostate Cancer February 2012 Phase 2
    NCT01560260 National Cancer Institute (NCI) Carney Complex|Chondrosarcoma|Gastrointestinal Stromal Tumor|Paraganglioma March 2012 Phase 2
    NCT01533181 National Cancer Institute (NCI) Recurrent Small Cell Lung Carcinoma February 2012 Phase 2
    NCT02057380 Astellas Pharma Global Development, Inc.|Astellas Pharma Inc Advanced Solid Tumors April 2014 Phase 2
    NCT01465815 OHSU Knight Cancer Institute|National Cancer Institute (NCI) Recurrent Skin Cancer|Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity|Squamous Cell Carcinoma of the Skin|Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity|Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity|Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity December 2011 Phase 1|Phase 2
    NCT01529684 Astellas Pharma Global Development, Inc.|Astellas Pharma Inc Advanced Solid Tumors|Pharmacokinetics of 14C-OSI-906 January 2012 Phase 1
    NCT01016860 University of Colorado, Denver Colorectal Cancer December 2009 Phase 1
    NCT00514306 Astellas Pharma Inc Advanced Solid Tumors June 2007 Phase 1
    NCT00924989 Astellas Pharma Inc Adrenocortical Carcinoma September 2009 Phase 3
    NCT00514007 Astellas Pharma Inc Advanced Solid Tumors December 2006 Phase 1
    NCT01221077 Astellas Pharma Inc Non Small Cell Lung Cancer|NSCLC December 2011 Phase 2
    NCT01334710 Emory University|OSI Pharmaceuticals Liver Cancer March 2011 Phase 2
    NCT01101906 Astellas Pharma Inc Advanced Hepatocellular Carcinoma (HCC) October 2010 Phase 2
    NCT01600807 Dana-Farber Cancer Institute Pancreatic Cancer, Metastatic Phase 1|Phase 2
    NCT00739453 Astellas Pharma Inc Advanced Solid Tumors October 2008 Phase 1
    NCT01205685 Vanderbilt-Ingram Cancer Center Hormone-sensitive Metastatic Breast Cancer May 2010 Phase 2
    NCT01186861 Astellas Pharma Inc Non-Small Cell Lung Cancer (NSCLC) With Nonprogression Following 4 Cycles of Platinum-based Chemotherapy December 2010 Phase 2
    NCT01154335 SCRI Development Innovations, LLC|Novartis Pharmaceuticals|OSI Pharmaceuticals Metastatic Colorectal Cancer July 2010 Phase 1
    NCT00889382 Astellas Pharma Inc Solid Tumors|Ovarian Cancer July 2009 Phase 1|Phase 2
    NCT01567384 Emory University|OSI Pharmaceuticals Cancer|Neoplasms|Tumors May 2012 Phase 1
    NCT01427205 M.D. Anderson Cancer Center|OSI Pharmaceuticals Head and Neck Cancer June 2013 Phase 2
    NCT01013506 Vanderbilt-Ingram Cancer Center|National Cancer Institute (NCI) Breast Cancer August 2009 Phase 2
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    References
    Preparing Stock Solutions
    Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
    1 mM 2.3725 mL 11.8627 mL 23.7254 mL
    5 mM 0.4745 mL 2.3725 mL 4.7451 mL
    10 mM 0.2373 mL 1.1863 mL 2.3725 mL
    Kinase Assay
    [1]

    Protein kinase assays are either performed in-house by ELISA-based assay methods (IGF-1R, IR, EGFR and KDR) or by a radiometric method with ATP at 100 µM concentration. In-house ELISA assays use poly(Glu:Tyr) as the substrate bound to the surface of 96-well assay plates and phosphorylation is detected using an antiphosphotyrosine antibody conjugated to horseradish peroxidase. The bound antibody is quantified using ABTS as the peroxidase substrate by measuring absorbance at 405/490 nm. All assays use purified recombinant kinase catalytic domains. Recombinant enzymes of human IGF-1R or EGFR are expressed as an NH2-terminal glutathione S-transferase fusion protein in insect cells and are purified in house. IC50 values are determined from the sigmoidal dose-response plot of percent inhibition versus log10 compound concentration. A minimum of three measurements, performed in duplicate, are carried out with in-house assays unless otherwise indicated. Linsitinib at a concentration of 1 µM is profiled versus a panel of kinases using the ProfilerProTM Kinase Selectivity Assay Kit. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [1]

    Linsitinib is dissolved in DMSO.

    For assays of cell proliferation, cells are seeded into 96-well plates in appropriate media containing FCS 10% and incubated for 3 days in the presence of Linsitinib at various concentrations. Inhibition of cell growth is determined by luminescent quantitation of intracellular ATP content using CellTiterGlo. Data is presented as a fraction of maximal proliferation, calculated by dividing the cellular density in the presence of varying concentrations of Linsitinib by the cellular density of control cells treated with vehicle (DMSO) only. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1]

    Cells are harvested from cell culture flasks during exponential cell growth, washed twice with sterile PBS to a suitable concentration before subcutaneous implantation on the right flank of female nu/nu CD-1 mice. Tumors are established to 200±50 mm3 in size before randomization into treatment groups of eight mice each for efficacy studies. Linsitinib or vehicle is administered orally as indicated. The %TGI values indicated are the median %TGI over the entire dosing period. TGI of at lease 505 is considered significant. Growth delay is calculated as T-C shere T and C are the times in days for mean tumor size in the treated (T) and control (C) groups to reach 400% of the initial tumor volume. Cures are excluded from this calculation. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    421.49

    Formula

    C₂₆H₂₃N₅O

    CAS No.

    867160-71-2

    Storage

    Please store the product under the recommended conditions in the Certificate of Analysis.

    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    10 mM in DMSO

    Linsitinib (OSI-906) is dissolved in 30% Solutol HS-15 at a concentration of 4.5 mg/mL[4].

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

    References

    Purity: 99.69%

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    Product Name:
    Linsitinib
    Cat. No.:
    HY-10191
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