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

Linsitinib (OSI-906) est un double inhibiteur de récepteur IGF-1 et de récepteur de l'insuline (IR) qui est puissant, sélectif et oralement biodisponible avec IC50 de 35 et 75 nM, respectivement.

Linsitinib (OSI-906) is a potent, selective and orally bioavailable dual inhibitor of the IGF-1 receptor and insulin receptor (IR) with IC50s of 35 and 75 nM, respectively.

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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Customer Review

Based on 40 publication(s) in Google Scholar

Top Publications Citing Use of Products

34 Publications Citing Use of MCE Linsitinib

WB

    Linsitinib purchased from MedChemExpress. Usage Cited in: Cell Metab. 2017 Apr 4;25(4):868-882.e5.  [Abstract]

    Western blot of indicated proteins in control β cells in the presence of 10 nM Insulin, 200 nM OSI-906 (IR/IGF1Ri), 50μM LY294002 (PI3Ki), 5μM MK-2206 (Akti), or 20μM U0126 (MEKi) for 24 hr. Bottom: intensity of the signals quantified by densitometry.

    Linsitinib purchased from MedChemExpress. Usage Cited in: Sci Rep. 2017 Jun 23;7(1):4119.  [Abstract]

    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.

    Linsitinib purchased from MedChemExpress. Usage Cited in: BMC Cancer. 2017 Dec 5;17(1):820.  [Abstract]

    OSI-906 inhibits p-IGF1R and IGF1R signaling factors in breast cancer cell-lines. HCC-1806 breast cancer cells are plated per well of a 6-well plate and cultured for 24 h and subsequently treated with OSI-906 (0.1, 0.4 and 1.6 μM) and/or SKI-II (4 μM) for 24 h. Protein lysates are collected and 20 μg of protein is used for immunoblot analysis to measure changes to IGF1R signaling and SphK1 steady-state protein expression levels.

    Linsitinib purchased from MedChemExpress. Usage Cited in: BMC Cancer. 2017 Dec 5;17(1):820.  [Abstract]

    OSI-906 inhibits p-IGF1R and IGF1R signaling factors in breast cancer cell-lines. 3 × 105 ER-positive MCF7 and ER-negative are plated per well of a 6-well plate and cultured for 24 h and subsequently treated with the OSI-906 (0.1, 0.4 and 1.6 μM) and/or SKI-II (4 μM) for 24 h. Protein lysates are collected and 20 μg of protein is used for immunoblot analysis to measure changes to IGF1R signaling and SphK1 steady-state protein expression levels.

    Linsitinib purchased from MedChemExpress. Usage Cited in: Department of Dental Pharmacology. Okayama University. 2015.

    The role of Semaphorin4D in bone invasion by oral cancer.

    Linsitinib purchased from MedChemExpress. Usage Cited in: Endocrinology. 2014 Jun;155(6):2102-11.  [Abstract]

    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.
    • Biological Activity

    • Protocol

    • Purity & Documentation

    • References

    • Customer Review

    Description

    Linsitinib (OSI-906) is a potent, selective and orally bioavailable dual inhibitor of the IGF-1 receptor and insulin receptor (IR) with IC50s of 35 and 75 nM, respectively[1].

    IC50 & Target

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

    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].

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

    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].

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

    Clinical Trial
    Molecular Weight

    421.49

    Formula

    C26H23N5O

    CAS No.
    Appearance

    Solid

    Color

    White to yellow

    SMILES

    O[C@@]1(C)C[C@@H](C2=NC(C3=CC=C4C=CC(C5=CC=CC=C5)=NC4=C3)=C6C(N)=NC=CN62)C1

    Shipping

    Room temperature in continental US; may vary elsewhere.

    Storage
    Powder -20°C 3 years
    4°C 2 years
    In solvent -80°C 2 years
    -20°C 1 year
    Solvent & Solubility
    In Vitro: 

    DMSO : 50 mg/mL (118.63 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

    Preparing
    Stock Solutions
    Concentration Solvent 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
    View the Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

    • Molarity Calculator

    • Dilution Calculator

    Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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    Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

    This equation is commonly abbreviated as: C1V1 = C2V2

    Concentration (start)

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    In Vivo:

    Select the appropriate dissolution method based on your experimental animal and administration route.

    For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
    To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
    The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

    • Protocol 1

      Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

      Solubility: ≥ 2.5 mg/mL (5.93 mM); Clear solution

      This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

      Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
    • Protocol 2

      Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in Saline)

      Solubility: ≥ 2.5 mg/mL (5.93 mM); Clear solution

      This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

      Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.

    For the following dissolution methods, please prepare the working solution directly. It is recommended to prepare fresh solutions and use them promptly within a short period of time.
    The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

    • Protocol 1

      Add each solvent one by one:  30% Solutol HS-15 in Saline

      Solubility: 5 mg/mL (11.86 mM); Suspended solution; Need ultrasonic

    In Vivo Dissolution Calculator
    Please enter the basic information of animal experiments:

    Dosage

    mg/kg

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    Number of animals

    Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
    Please enter your animal formula composition:
    %
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    Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
    The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
    Calculation results:
    Working solution concentration: mg/mL
    Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
    The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
    Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
     If the continuous dosing period exceeds half a month, please choose this protocol carefully.
    Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
    Purity & Documentation

    Purity: 99.83%

    References
    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]

    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

    Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

    Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
    DMSO 1 mM 2.3725 mL 11.8627 mL 23.7254 mL 59.3134 mL
    5 mM 0.4745 mL 2.3725 mL 4.7451 mL 11.8627 mL
    10 mM 0.2373 mL 1.1863 mL 2.3725 mL 5.9313 mL
    15 mM 0.1582 mL 0.7908 mL 1.5817 mL 3.9542 mL
    20 mM 0.1186 mL 0.5931 mL 1.1863 mL 2.9657 mL
    25 mM 0.0949 mL 0.4745 mL 0.9490 mL 2.3725 mL
    30 mM 0.0791 mL 0.3954 mL 0.7908 mL 1.9771 mL
    40 mM 0.0593 mL 0.2966 mL 0.5931 mL 1.4828 mL
    50 mM 0.0475 mL 0.2373 mL 0.4745 mL 1.1863 mL
    60 mM 0.0395 mL 0.1977 mL 0.3954 mL 0.9886 mL
    80 mM 0.0297 mL 0.1483 mL 0.2966 mL 0.7414 mL
    100 mM 0.0237 mL 0.1186 mL 0.2373 mL 0.5931 mL
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    • Do most proteins show cross-species activity?

      Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

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