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 (IC
50s = 35 and 75 nM, respectively). It also inhibits InsR-
related receptor (IC
50 = 75 nM) but is without effect (IC
50 > 10 μM) against a large panel of other kinases. Linsitinib inhibits proliferation of a variety of tumor cell lines
in vitro and has antitumor efficacy in an IGF-1R-driven xenograft mouse model when administered orally. A rapid, non-invasive method to predict the pharmacodynamic response to linsitinib has been reported.
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.
References
[1] MARK J MULVIHILL. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor.[J]. Future medicinal chemistry, 2009, 1 6: 1153-1171. DOI:
10.4155/fmc.09.89[2] JOHANNA C BENDELL. 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.[J]. Investigational New Drugs, 2015, 33 1: 187-193. DOI:
10.1007/s10637-014-0177-3[3] C. PIVONELLO. The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma[J]. Oncotarget, 2016, 7 1: 9718-9731. DOI:
10.18632/oncotarget.6836[4] YONGIK LEE. Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells.[J]. Molecular Carcinogenesis, 2016, 55 5: 991-1001. DOI:
10.1002/mc.22342[5] V. MACAULAY. Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors[J]. Clinical Cancer Research, 2016, 19 1: 2897-2907. DOI:
10.1158/1078-0432.ccr-15-2218[6] KLAAS DE LINT. Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R.[J]. Molecular Cancer Therapeutics, 2016: 1545-1556. DOI:
10.1158/1535-7163.mct-15-0865
