Linsitinib (OSI-906)

Catalog No.S1091 Batch:S109107

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Technical Data

Formula

C26H23N5O
Molecular Weight 421.49 CAS No. 867160-71-2
Solubility (25°C)* In vitro DMSO 84 mg/mL (199.29 mM)
Water Insoluble
Ethanol Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Linsitinib (OSI-906) 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)
35 nM 75 nM 75 nM
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]
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]

Protocol (from 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

  • Dosages

    25 mg / kg and 75 mg / kg

  • Administration

    Orally administrated at once-daily oral dose for 14 days

Customer Product Validation

Data from [Cancer Res, 2013, 73, 834-843]

Data from [Cancer Res, 2011, 71, 6773-84]

,

Data from [Data independently produced by , , Nature, 2018, 560(7719):499-503]

Selleck's Linsitinib (OSI-906) has been cited by 203 publications

Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2 [ Nat Commun, 2024, 15(1):6525] PubMed: 39117630
Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion [ Nat Commun, 2024, 15(1):828] PubMed: 38280853
Acinar-ductal cell rearrangement drives branching morphogenesis of the murine pancreas in an IGF/PI3K-dependent manner [ Dev Cell, 2024, 59(3):326-338.e5] PubMed: 38237591
Insulin receptor signaling engages bladder urothelial defenses that limit urinary tract infection [ Cell Rep, 2024, 43(4):114007] PubMed: 38517889
CK2 activity is crucial for proper glucagon expression [ Diabetologia, 2024, 10.1007/s00125-024-06128-1] PubMed: 38503901
Insulin receptor substrate 1 is a novel member of EGFR signaling in pancreatic cells [ Eur J Cell Biol, 2024, 103(4):151457] PubMed: 39326351
Novel therapeutic strategies targeting bypass pathways and mitochondrial dysfunction to combat resistance to RET inhibitors in NSCLC [ Biochim Biophys Acta Mol Basis Dis, 2024, 1870(6):167249] PubMed: 38768929
Functional Investigation of IGF1R Mutations in Multiple Myeloma [ Cancers (Basel), 2024, 16(11)2139] PubMed: 38893258
Modeling unveils sex differences of signaling networks in mouse embryonic stem cells [ Mol Syst Biol, 2023, e11510.] PubMed: 37735975
Targeting the E3 ligase NEDD4 as a novel therapeutic strategy for IGF1 signal pathway-driven gastric cancer [ Oncogene, 2023, 42(14):1072-1087] PubMed: 36774408

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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