Linsitinib

• CAT Number: I005217
• CAS Number: 867160-71-2
• Molecular Formula: C26H23N5O
• Molecular Weight: 421.49
• Purity: ≥95%
• Synonyms: 3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol
• 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)
• InChIKey: PKCDDUHJAFVJJB-UHFFFAOYSA-N
• SMILES: CC1(CC(C1)C2=NC(=C3N2C=CN=C3N)C4=CC5=C(C=C4)C=CC(=N5)C6=CC=CC=C6)O

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[1].
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].
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].

Reference

[1]. Mulvihill MJ, et al. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and IR. Future Med Chem. 2009 Sep;1(6):1153-71.
 [Content Brief]

[2]. 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.
 [Content Brief]

[3]. 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.
 [Content Brief]