OSI-906 (Linsitinib)

OSI-906 (Linsitinib) is a selective inhibitor of IGF-1R with IC50 of 35 nM in cell-free assays; modestly potent to InsR with IC50 of 75 nM, and no activity towards Abl, ALK, BTK, EGFR, FGFR1/2, PKA etc. Phase 3.

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OSI-906 (Linsitinib) Chemical Structure

OSI-906 (Linsitinib) Chemical Structure
Molecular Weight: 421.49

Validation & Quality Control

Customer Product Validation(3)

Quality Control & MSDS

Related Compound Libraries

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Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description OSI-906 (Linsitinib) is a selective inhibitor of IGF-1R with IC50 of 35 nM in cell-free assays; modestly potent to InsR with IC50 of 75 nM, and no activity towards Abl, ALK, BTK, EGFR, FGFR1/2, PKA etc. Phase 3.
Targets IGF-1R [1]
(Cell-free assay)
Insulin Receptor [1]
(Cell-free assay)
IRR [1]
(Cell-free assay)
Abl [1]
(Cell-free assay)

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IC50 35 nM 75 nM 75 nM >10 μM
In vitro OSI-906 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. OSI-906 enables an intermediate conformation of the target protein through interactions with the C-helix. OSI-906 displays favorable metabolic stability in liver microsomes. OSI-906 fully inhibits both IR and IGF-1R phosphorylation at a concentration of 1 μM. OSI-906 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]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
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... Click to View More Cell Line Experimental Data

In vivo OSI-906 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. OSI-906 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. OSI-906 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 OSI-906 dose. OSI-906 elevates the blood glucose levels at a dose of 25 mg/kg after 12 days administration. OSI-906 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] OSI-906 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. OSI-906 inhibits the growth of tumors in NCI-H292 xenograft mouse model. [2]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Protein kinase biochemical assays Protein kinase assays are either performed in-house by ELISA-based assay methods (IGF-1R, IR, EGFR and KDR) or at Upstate Inc. 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. OSI-906 at a concentration of 1 µM is profiled versus a panel of kinases using the ProfilerProTM Kinase Selectivity Assay Kit.

Cell Assay: [1]

Cell lines MCF7, NCI-H292, Colo-205, HT29, H358, H1703, BxPC3, A673, SW620, DU4475, HepG2 and Hepa-1, RKO 3T3/hulGF-IR and H292 cells
Concentrations 0.02-0.8 μM
Incubation Time 3 days
Method 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 OSI-906 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 OSI-906 by the cellular density of control cells treated with vehicle (DMSO) only.

Animal Study: [1]

Animal Models IGF-1R-driven full-length human IGF-1R (LISN) xenograft mouse model
Formulation 25 mM tartaric acid
Dosages 25 mg / kg and 75 mg / kg
Administration Orally administrated at once-daily oral dose for 14 days

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Mulvihill MJ, et al. Future Med Chem, 2009, 1(6), 1153-1171.

[2] McKinley ET, et al. Clin Cancer Res, 2011, 17(10), 3332-3340.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-01-10)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02057380 Active, not recruiting Advanced Solid Tumors Astellas Pharma Global Development, Inc.|Astellas Pharma Inc April 2014 Phase 2
NCT02546544 Recruiting Relapsed Ewing Sarcoma|Refractory Ewing Sarcoma University of Oxford|European Organisation for Research a  ...more University of Oxford|European Organisation for Research and Treatment of Cancer - EORTC|European Commission|Astellas Pharma Inc|Oxford University Hospitals NHS Trust March 2014 Phase 2
NCT01427205 Withdrawn Head and Neck Cancer M.D. Anderson Cancer Center|OSI Pharmaceuticals June 2013 Phase 2
NCT01567384 Withdrawn Cancer|Neoplasms|Tumors Emory University|OSI Pharmaceuticals May 2012 Phase 1
NCT01560260 Active, not recruiting Carney Complex|Chondrosarcoma|Gastrointestinal Stromal Tumor|Paraganglioma National Cancer Institute (NCI) March 2012 Phase 2

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Chemical Information

Download OSI-906 (Linsitinib) SDF
Molecular Weight (MW) 421.49
Formula

C26H23N5O

CAS No. 867160-71-2
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 84 mg/mL (199.29 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (1s,3s)-3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

Customer Product Validation (3)


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Rating
Source Cancer Res 2013 73, 834-843. OSI-906 (Linsitinib) purchased from Selleck
Method Cell proliferation and growth assays
Cell Lines PFR3 cells
Concentrations 1 μM
Incubation Time
Results The IC50 of PFR3 cells for PF299804 was more than 100 fold lower with the combination of OSI-90 than with PF00299804 alone.

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Rating
Source Cancer Res 2011 71, 6773-84. OSI-906 (Linsitinib) purchased from Selleck
Method [18 F]FDG –PET/ Western blot
Cell Lines MCF-7 cells/athymic mice
Concentrations 50 mg/kg/day
Incubation Time 6 weeks
Results mice without palpable tumors were randomized to treatment with vehicle or OSI-906. Six of 20 control mice (30%) developed tumors, whereas none of the 20 OSI-906–treated mice did (Fig. A). OSI-906 inhibited tumor growth compared with vehicle (Fig. B; P < 0.05). OSI-906–treated tumors exhibited markedly lower levels of phosphorylated IGF-IR, InsR, IRS-1, AKT, and S6 compared with vehicle controls (Fig. C). FDG uptake was significantly decreased 4 hours after a single dose of OSI-906 com-pared with baseline (Fig. D)

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Rating
Source OSI-906 (Linsitinib) purchased from Selleck
Method Flow cytometry/ Western Blotting
Cell Lines CLL B cells
Concentrations 1 µM
Incubation Time 24 h
Results three structurally unrelated IGF1R inhibi tors AG1024, Picropodophyllin (PPP) and linsitinib significantly reduced the cellular viability of primary CLL cells ( Figure A) and reduced levels of phosphorylated IGF1R and IRS-1 (Figure B,C). AG1024, which showed the strongest effect on viability, caused a dose-dependent decrease in the levels of phosphorylated Src, PI3K, Akt, MEK and ERK (Figure D).

Product Use Citation (15)

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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