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Purity: ≥98%
Linsitinib (formerly OSI-906; OSI 906) is a firs-in-class, ATP-competitive and orally bioavailable dual inhibitor of and insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) with potential antitumor activity. It exhibits modest potency against InsR with an IC50 of 75 nM, and it has no activity against other kinases like Abl, ALK, BTK, EGFR, FGFR1/2, PKA, and so on. In cell-free assays, it inhibits IGF-1R with an IC50 of 35 nM.
| Targets |
IGF-1R (IC50 = 35 nM); InsR (IC50 = 75 nM)
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| ln Vitro |
OSI-906 inhibits the activation of downstream signaling proteins Akt, ERK1/2, and S6 kinase, as well as IGF-1R autophosphorylation, with an IC50 of 0.028 to 0.13 μM. The C-helix interacts with OSI-906 to allow the target protein to adopt an intermediate conformation. Liver microsomes show that OSI-906 has a favorable metabolic stability. At a concentration of 1 μM, OSI-906 completely inhibits both IGF-1R and IR phosphorylation. Multiple tumor cell lines, such as colorectal cancer (CRC) and non-small-cell lung cancer (NSC), are inhibited in proliferating by OSI-906, with an EC50 ranging from 0.021 to 0.810 μM.[1]
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| ln Vivo |
OSI-906 suppresses tumor growth in a xenograft mouse model driven by IGF-1R, showing 100% TGI and 55% regression at 75 mg/kg and 60% TGI and no regression at 25 mg/kg. In dogs, rats, and mice, OSI-906 administration causes varying elimination half-lives of the compound; these half-lives are 1.18 hours, 2.64 hours, and 2.14 hours, respectively. The administration of OSI-906 to female Sprague-Dawley rats and female CD-1 mice at varying single doses once daily indicates that the Vmax does not correspond with the OSI-906 dosage. After 12 days of administration, a dose of 25 mg/kg of OSI-906 raises blood glucose levels. In an IGF-1R-driven full-length human IGF-1R (LISN) xenograft mouse model, OSI-906 administered at a single dose of 75 mg/kg achieves maximal inhibition of IGF-1R phosphorylation (80%) between 4 and 24 hours with plasma drug concentrations of 26.6-4.77 μM.[1] In NCI-H292 xenograft mice, OSI-906 given as a single dose at 60 mg/kg inhibits glucose uptake at 2, 4, and 24 hours after treatment in vivo. In the NCI-H292 xenograft mouse model, OSI-906 inhibits the growth of tumors.[2]
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| Enzyme Assay |
Protein kinase assays are conducted at Upstate Inc. using a radiometric method with ATP at a concentration of 100 µM, or in-house using ELISA-based assay methods (IGF-1R, IR, EGFR, and KDR). A horseradish peroxidase-conjugated antiphosphotyrosine antibody is used in house ELISA assays to detect phosphorylation. The substrate, poly(Glu:Tyr), is bound to the surface of 96-well assay plates. By measuring absorbance at 405 / 490 nm, the bound antibody is quantified using ABTS as the peroxidase substrate. Purified recombinant kinase catalytic domains are used in all assays. Human IGF-1R or EGFR recombinant enzymes are purified in-house and expressed in insect cells as an NH2-terminal glutathione S-transferase fusion protein. The sigmoidal dose–response plot of percent inhibition versus log10 compound concentration is used to calculate IC50 values. Unless otherwise specified, a minimum of three measurements are made using internal assays and are done in duplicate. OSI-906 is profiled against a panel of kinases using the ProfilerProTM Kinase Selectivity Assay Kit at a concentration of 1 µM.
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| Cell Assay |
Cells are seeded into 96-well plates in the proper media containing 10% FCS for cell proliferation assays. The cells are then incubated for three days in the presence of varying concentrations of OSI-906. Using CellTiterGlo, luminescent quantification of intracellular ATP content is used to determine inhibition of cell growth. The cellular density of control cells treated with vehicle (DMSO) alone is divided by the cellular density of cells in the presence of different concentrations of OSI-906 to determine the fraction of maximal proliferation, which is used to present the data.
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| Animal Protocol |
Before being subcutaneously implanted on the right flank of female nu/nu CD-1 mice, cells are taken from cell culture flasks during exponential cell growth and once again cleaned with sterile PBS to an appropriate concentration. Prior to being randomly assigned to treatment groups consisting of eight mice each for efficacy studies, tumors are allowed to grow to a size of 200±50 mm3. It is recommended to take linatinib or the vehicle orally. For the duration of the dosage period, the %TGI values displayed are the median %TGI. Significantity is defined as TGI of at least 505. T-C is the growth delay, where T and C are the number of days it takes for the mean tumor size in the treated (T) and control (C) groups to increase to 400% of the initial tumor volume. In this computation, cures are not included.
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| References |
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| Additional Infomation |
3-[8-amino-1-(2-phenyl-7-quinolinyl)-3-imidazo[1,5-a]pyrazinyl]-1-methyl-1-cyclobutanol is a member of quinolines and a member of cyclobutanes.
An orally bioavailable small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) with potential antineoplastic activity. IGF-1R inhibitor OSI-906 selectively inhibits IGF-1R, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis. Linsitinib is an orally bioavailable small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) with potential antineoplastic activity. 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, IGF-1R stimulates cell proliferation, enables oncogenic transformation, and suppresses apoptosis. Drug Indication Investigated for use/treatment in cancer/tumors (unspecified) and solid tumors. Mechanism of Action IGF-1R stimulates proliferation, enables onogenic transformation, and suppresses apoptosis. Inhibitors of IGF-1R are expected to have broad utility in oncology since the over-expression of IGF-1R and/or its ligands or the down-regulation of ligand binding proteins occurs in numerous human malignancies including lung, colon, breast, prostate, brain and skin cancers. In addition, signaling through the IGF system has been implicated in protecting tumor cells from apoptosis induced by anti-cancer treatments such as cytotoxic agents and EGFR inhibitors. Pharmacodynamics In laboratory studies of 28 human tumor cell lines, OSI-906 reduced growth of 15 cell lines representative of colorectal, lung, breast, pancreatic, and pediatric tumors and in mouse models. OSI-906 was particularly effective against tumors that are highly IGF-dependent such as colorectal cancers. According to the researchers, OSI-906 not only slowed tumor growth in mice, but decreased the size of some pre-existing tumors. |
| Molecular Formula |
C26H23N5O
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| Molecular Weight |
421.49
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| Exact Mass |
421.19
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| Elemental Analysis |
C, 74.09; H, 5.50; N, 16.62; O, 3.80
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| CAS # |
867160-71-2
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| Related CAS # |
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| PubChem CID |
11640390
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| Appearance |
White to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.748
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| LogP |
3.23
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
32
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| Complexity |
663
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| Defined Atom Stereocenter Count |
0
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| SMILES |
NC1=NC=CN2C([C@@H]3C[C@@](O)(C)C3)=NC(=C12)C1C=CC2C=CC(C3C=CC=CC=3)=NC=2C=1
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| InChi Key |
PKCDDUHJAFVJJB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H23N5O/c1-26(32)14-19(15-26)25-30-22(23-24(27)28-11-12-31(23)25)18-8-7-17-9-10-20(29-21(17)13-18)16-5-3-2-4-6-16/h2-13,19,32H,14-15H2,1H3,(H2,27,28)
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| Chemical Name |
3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol
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| Synonyms |
OSI906; Linsitinib; OSI-906; OSI 906
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 30% PEG 400+0.5% Tween 80+5% Propylene glycol: 30 mg/mL Solubility in Formulation 4: 5 mg/mL (11.86 mM) in 30% Solutol HS-15 (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05276063 | Recruiting | Drug: Linsitinib Drug: Placebo |
IGF1R Exophthalmos |
Sling Therapeutics, Inc. | July 1, 2022 | Phase 2 Phase 3 |
| NCT02057380 | Completed | Drug: linsitinib Drug: erlotinib |
Advanced Solid Tumors | Astellas Pharma Global Development, Inc. |
April 16, 2014 | Phase 2 |
| NCT02546544 | Completed | Drug: Linsitinib | Relapsed Ewing Sarcoma Refractory Ewing Sarcoma |
University of Oxford | March 2014 | Phase 2 |
| NCT00889382 | Completed | Drug: OSI-906 Drug: Paclitaxel |
Ovarian Cancer Solid Tumors |
Astellas Pharma Inc | August 5, 2009 | Phase 1 Phase 2 |
| NCT01154335 | Completed | Drug: OSI-906 Drug: Everolimus |
Metastatic Colorectal Cancer | SCRI Development Innovations, LLC | July 2010 | Phase 1 |
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