Linsitinib
Linsitinib Basic information
- Product Name:
- Linsitinib
- Synonyms:
-
- OSI-906
- cis-3-[8-Amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol
- Linsitinib
- OSI-906 Linsitinib
- Cyclobutanol, 3-[8-aMino-1-(2-phenyl-7-quinolinyl)iMidazo[1,5-a]pyrazin-3-yl]-1-Methyl-, cis-
- OSI 906AA
- (1S,3r)-3-((S)-8-aMino-1-(2-phenylquinolin-7-yl)-2,3-dihydroiMidazo[1,5-a]pyrazin-3-yl)-1-Methylcyclobutanol
- (1s,3r)-3-[4-aMino-3-(2-phenylquinolin-7-yl)iMidazo[1,5-a]pyrazin-1-yl]-1-Methylcyclobutan-1-ol
- CAS:
- 867160-71-2
- MF:
- C26H23N5O
- MW:
- 421.49
- EINECS:
- 1533716-785-6
- Product Categories:
-
- Tyrosine Kinase Inhibitors
- Inhibitors
- Amines
- Aromatics
- Heterocycles
- Intermediates & Fine Chemicals
- Pharmaceuticals
- Mol File:
- 867160-71-2.mol
Linsitinib Chemical Properties
- Melting point:
- >175°C (dec.)
- Density
- 1.39
- storage temp.
- -20°C
- solubility
- Soluble in DMSO (up to 30 mg/ml)
- form
- solid
- pka
- 14.84±0.40(Predicted)
- color
- Yellow
- Stability:
- Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 2 months.
Linsitinib Usage And Synthesis
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.
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.
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. 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.
Description
The binding of insulin-like growth factor 1 (IGF-1) to the IGF-1 receptor (IGF-1R) promotes cell growth while inhibiting apoptotic pathways. Overexpression of IGF-1R is found in certain solid tumors and hematologic neoplasias. However, insulin receptor (InsR) signaling can compensate for IGF-1R inhibition. Linsitinib is a dual inhibitor of IGF-1R and InsR kinases (IC50s = 35 and 75 nM, respectively). It also inhibits InsR-
Uses
Linsitinib is a small-molecule dual insulin-like growth factor-1 receptor (IGF-IR) and insulin receptor (IR) kinase inhibitor. IGF-I receptor (IGF-IR) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies and thus Linsitinib may be a useful anticancer agent. Potent IGF-1R inhibitor.
Definition
ChEBI: 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.
target
IGF-1R
storage
Store at -20°C
References
1) Mulvihill?et al.?(2009),?Discovery of OSI-906: a selective and orally efficacious inhibitor of the IGF-1 receptor and insulin receptor; Future Med. Chem.?1?1153 2) Bendell?et al.?(2015),?A phase Ib study of linsitinib (OSI-906), a dual inhibitor of IGF-1R and IR tyrosine kinase, in combination with everolimus as treatment for patients with refractory metastatic colorectal cancer; Invest. New Drugs?33?187 3) Pivonello?et al.?(2016),?The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma?; Oncotarget?7?9718 4) Lee?et al.?(2016),?Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells; Mol. Carcinog.?55?991 5) Macaulay?et al.?(2016),?Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors; Clin. Cancer Res.?22?2897 6) De Lint?et al.?(2016),?Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R; Mol. Cancer Ther.?15?1545
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- Product Name:OSI-906 (Linsitinib)
CAS:867160-71-2
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CAS:867160-71-2
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- Product Name:Linsitinib
CAS:867160-71-2
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- Products Intro
- Product Name:Linsitinib (OSI-906)
CAS:867160-71-2
Purity:98+% Package:1g;5g;10g Remarks:C13962
- Tel
- 0573-85285100 18627885956
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- Products Intro
- CAS:867160-71-2
Purity:98% (HPLC or GC) Package:25g,100g,500g;1kg