Linsitinib | CAS:867160-71-2

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Name:Linsitinib; OSI-906
Cat. No. :CS-0242
CAS No. :867160-71-2
Formula:C26H23N5O
M. Wt. : 421.49
Solubility:10 mM in DMSO

Linsitinib is a selective inhibitor of IGF-1R with IC50 of 35 nM, and modestly potent to InsR with IC50 of 75 nM, and has no activity towards Abl, ALK, BTK, EGFR, FGFR1/2, PKA etc.IC50 & Target: IC50: 35 nM (IGF-1R), 75 nM (InsR)In Vitro: Linsitinib 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. Linsitinib enables an intermediate conformation of the target protein through interactions with the C-helix. Linsitinib displays favorable metabolic stability in liver microsomes. Linsitinib fully inhibits both IR and IGF-1R phosphorylation at a concentration of 1 μM. Linsitinib 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: Linsitinib 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. Linsitinib 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. Linsitinib 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 Linsitinib dose. Linsitinib elevates the blood glucose levels at a dose of 25 mg/kg after 12 days administration. Linsitinib 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]. Linsitinib 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. Linsitinib inhibits the growth of tumors in NCI-H292 xenograft mouse model[2]. 

Mulvihill MJ, et al. 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. Tajima K, et al. Metabolic recovery of lipodystrophy, liver steatosis, and pancreatic β cell proliferation after the withdrawal of OSI-906. Sci Rep. 2017 Jun 23;7(1):4119. McKinley ET, et al. 18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer. Clin Cancer Res. 2011 May 15;17(10):3332-40. Li W, et al. Effectiveness of inhibitor rapamycin, saracatinib, linsitinib and JNJ-38877605 against human prostate cancer cells. Int J Clin Exp Med. 2015 Apr 15;8(4):6563-7. Mayu Kyohara, et al. Serum quantitative proteomic analysis reveals soluble EGFR to be a marker of insulin resistance in male mice and humans. Endocrinology. 2017 Oct 5.