tcsc0242 Linsitinib

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].