IGF-1R (insulin-like growth factor-1 receptor) plays a key role in transformation, growth and survival of malignant cells, and has been considered as a general and promising target for cancer treatment. Linsitinib is a potent and selective IGF-1R receptor with IC50 value of 35nM, also show inhibitory effect against Insulin receptor and insulin receptor-related receptor with IC50 values of 75nM for both (measured by purified recombinant kinase activity). Treatment with Linsitinib at concentration ranging in 0.01-1μM for 2h could dose-dependently inhibited autophosphorylation of IGF-1R, at phosphorylation of the downstream, including AKT, ERK and p70S6K with IC50 of 24nM, 130nM, 28nM and 60nM, respectively, in 3T3/huIGF-1R (LISN) cells. Also the inhibition on phosphorylation of both IGF-1R and IR by Linsitinib was shown in HT-29 and Colo-205 cells. The antiproliferative effect of Linsitinib could be observed in a panel of cell lines from various tumor types with IC50 ranging in 0.021-0.81μM, including HT29, Colo205, SW620 (colorectal), DU4475, MCF7 (breast), 3T3/huIGF-1R (mouse fibroblast), H358, H292 (non-small-cell lung), BxPC3 (pancreatic) and A673 (rhabdomyosarcoma) cell lines. A further study showed that a panel of non-small-cell lung cancer and colorectal cancer (CRC) tumor cell lines exhibiting an epithelial phenotype exhibited greater sensitivity to Linsitinib than those tumor cells that have undergone an epithelial–mesenchymal transition. A single oral dose of 75mg/kg Linsitinib inhibited the autophosphorylation of IGF-1R 2-24h after dose in LISN tumor xenograft models, suggesting the pharmacodynamics of this compound. Oral administration of Linsitinib at 75mg/kg once-daily for 12 days significantly inhibit tumor growth in a LISN xenograft model[1].
作用机制
Linsitinib can attach to the ATP-binding pocket of tyrosine kinase receptors, causing dual inhibition of both IR and IGF-1R.[1]
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