Linsitinib

IGF1R/IR inhibitor,potent and novel CAS# 867160-71-2

Linsitinib

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Quality Control of Linsitinib

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Chemical structure

Linsitinib

3D structure

Chemical Properties of Linsitinib

Cas No. 867160-71-2 SDF Download SDF
PubChem ID 11640390 Appearance Powder
Formula C26H23N5O M.Wt 421.51
Type of Compound N/A Storage Desiccate at -20°C
Synonyms OSI-906
Solubility DMSO : 62.5 mg/mL (148.28 mM; Need ultrasonic)
Chemical Name 3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol
SMILES CC1(CC(C1)C2=NC(=C3N2C=CN=C3N)C4=CC5=C(C=C4)C=CC(=N5)C6=CC=CC=C6)O
Standard InChIKey PKCDDUHJAFVJJB-UHFFFAOYSA-N
Standard InChI 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Linsitinib

DescriptionOSI-906 (Linsitinib) is a selective inhibitor of IGF-1R with IC50 of 35 nM; modestly potent to InsR with IC50 of 75 nM.
TargetsIGF-1RInsR    
IC5035 nM75 nM    

Protocol

Cell experiment: [1]

Cell lines

HepG2, Hep3B, Huh-7, PLC/PRF/5, SNU-387 and SNU-423 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

3 μM, 20 hours

Applications

All 6HCCcell lines showed higher IR phosphorylation than IGF-1R, suggesting the significance of IR activity in HCC. Furthermore, all 3 HCC cell lines (HepG2, Hep3B, and HuH-7) that are sensitive to OSI-906 had much higher phosphorylation levels of both IGF-1R and IR than insensitive cell lines. This suggests that sensitivity to OSI-906 associates with activation of both IGF-1R and IR in HCC cell lines.

Animal experiment: [2]

Animal models

Female athymic nude mice injected with NCI-H292 or NCI-H441 cells

Dosage form

Oral administration, 60 mg/kg

Application

The NCI-H292 xenografts (sensitive to OSI-906 treatment) show a significant decrease (p<0.05) in 18FDG uptake at 2, 4 and 24 hours post dosing with OSI-906 compared to vehicle treated controls. NCI-H441 xenografts (insensitive to OSI-906 treatment) did not demonstrate a significant change in uptake of 18FDG at any time point evaluated. The decreased %ID/g in the NCI-H292 xenografts is suggestive of a rapid PD effect observed by 18FDG imaging mediated by the inhibition of IGF-1R and IR pathways by OSI-906. Conversely, for the NCI-H441 xenograft model no difference in uptake of the radiotracer was observed in the tumor samples between vehicle controls and the OSI-906 treatment group.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Zhao H, Desai V, Wang J, et al. Epithelial–Mesenchymal Transition Predicts Sensitivity to the Dual IGF-1R/IR Inhibitor OSI-906 in Hepatocellular Carcinoma Cell Lines. Molecular cancer therapeutics, 2012, 11(2): 503-513.

[2] McKinley E T, Bugaj J E, Zhao P, et al. 18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer. Clinical Cancer Research, 2011, 17(10): 3332-3340.

Linsitinib Dilution Calculator

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Preparing Stock Solutions of Linsitinib

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3724 mL 11.8621 mL 23.7242 mL 47.4485 mL 59.3106 mL
5 mM 0.4745 mL 2.3724 mL 4.7448 mL 9.4897 mL 11.8621 mL
10 mM 0.2372 mL 1.1862 mL 2.3724 mL 4.7448 mL 5.9311 mL
50 mM 0.0474 mL 0.2372 mL 0.4745 mL 0.949 mL 1.1862 mL
100 mM 0.0237 mL 0.1186 mL 0.2372 mL 0.4745 mL 0.5931 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Linsitinib

Linsitinib (OSI-906) is a potent and novel small-molecule inhibitor inhibiting insulin receptor (IR) and IGF-1 receptor (IGF-1R) kinases with IC50 value of 75nM and 35nM, respectively1.

Studies in 3T3/hulGF-1R(LISN) cells showed that linsitinib inhibits the ligant-dependent autophosphorylation of IGF-1R and its downstream signaling pathways including pERK1/2, pAKT, p-p70S6K. Linsitinib showed anti-proliferative effects in different cancer cell lines including colorectal cells (SW620), breast tumor cells (DY4475) and mouse fibroblast cells (3T3/hulGF-1R) with EC50 of 21nM, 86nM, and 78nM, respectively1.

Linsitinib administrated orally in LISN derived xenograft model has been shown to suppress the tumor growth in a dose-dependent manner 1.

References:
1. Mulvihill MJ1, Cooke A, Rosenfeld-Franklin M, Buck E, Foreman K, Landfair D, O'Connor M, Pirritt C, Sun Y, Yao Y, Arnold LD, Gibson NW, Ji QS. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem. 2009 Sep;1(6):1153-71

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References on Linsitinib

A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer.[Pubmed:27694157]

Oncologist. 2016 Oct;21(10):1163-1164.

LESSONS LEARNED: Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials.Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC.Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, Linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients. BACKGROUND: Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC. METHODS: In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m(2) intravenously or 2.3 mg/m(2) orally, daily for 5 days for 4 cycles) or Linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0-2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to Linsitinib was allowed at progression. RESULTS: Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received Linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with Linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5-3.6) and 1.2 (95% CI, 1.1-1.4) months for topotecan and Linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2-7.6) and 3.4 (95% CI, 1.8-5.6) months for topotecan and Linsitinib, respectively (p = .71). Grade 3/4 adverse events (>5% incidence) included anemia, thrombocytopenia, neutropenia/leukopenia, diarrhea, fatigue, dehydration, and hypokalemia for topotecan; and thrombocytopenia, fatigue, and alanine aminotransferase/aspartate aminotransferase elevations for Linsitinib. CONCLUSION: Linsitinib was safe but showed no clinical activity in unselected, relapsed SCLC patients.

Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non-Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations.[Pubmed:27686971]

Clin Lung Cancer. 2017 Jan;18(1):34-42.e2.

INTRODUCTION: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non-small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes. PATIENTS AND METHODS: We performed a randomized, double-blind, placebo-controlled phase II study of Linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR-mutation positive, advanced non-small-cell lung cancer. Patients received Linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival. RESULTS: After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the Linsitinib arm. The median progression-free survival for the Linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were Linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results. CONCLUSION: Adding Linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.

Mass balance, pharmacokinetics, and metabolism of linsitinib in cancer patients.[Pubmed:26972330]

Cancer Chemother Pharmacol. 2016 Apr;77(4):829-37.

PURPOSE: This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-Linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of Linsitinib after multiple-dose administration was assessed in those patients who wished to continue treatment beyond the single (14)C-Linsitinib dose. METHODS: Five patients received a single oral dose of 150 mg (14)C-Linsitinib, followed by collection of blood, plasma, urine, and feces for 10 days. The collected material was analyzed for total radioactivity, Linsitinib, and metabolites. The safety of 150 mg of unlabeled Linsitinib administered twice daily until disease progression was also assessed. RESULTS: The median time to reach the maximum plasma concentration of Linsitinib was 3.0 h, median maximum plasma concentration was 1789 ng/mL, median terminal half-life was 2.4 h, and median apparent oral clearance was 12.45 L/h. After a single dose of (14)C-Linsitinib, 5.44 and 76.4 % of mean total radioactivity administered were recovered in urine and feces, respectively. Eighteen Linsitinib metabolites (M1-M18) were detected in plasma, urine, and feces samples, and their structures were elucidated. The main metabolic reactions of Linsitinib in humans were oxidation and sulfate conjugation. Linsitinib was well tolerated after a single dose of (14)C-Linsitinib, and fatigue was the most frequent adverse event following multiple doses of unlabeled Linsitinib. CONCLUSIONS: (14)C-Linsitinib is rapidly absorbed and extensively metabolized. Linsitinib excretion via bile into feces is the predominant elimination route from plasma with minor renal elimination.

Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors.[Pubmed:26831715]

Clin Cancer Res. 2016 Jun 15;22(12):2897-907.

PURPOSE: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of Linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib. EXPERIMENTAL DESIGN: This open-label, dose-escalation study investigated Linsitinib schedules S1: once daily intermittent (days 1-3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100-150 mg once daily; and a non-small cell lung cancer (NSCLC) expansion cohort. RESULTS: Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for Linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug-drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51%), and 28 of 91 (31%) patients were on study >12 weeks. CONCLUSIONS: The Linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897-907. (c)2016 AACR.

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.

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