Linsitinib

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.^1,2 However, insulin receptor (InsR) signaling can compensate for IGF-1R inhibition.³ Linsitinib is a dual inhibitor of IGF-1R and InsR kinases (IC₅₀s = 35 and 75 nM, respectively).⁴ It also inhibits InsR-related receptor (IC₅₀ = 75 nM) but is without effect (IC₅₀ > 10 µM) against a large panel of other kinases.⁴ 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.⁴ A rapid, non-invasive method to predict the pharmacodynamic response to linsitinib has been reported.³

WARNING This product is not for human or veterinary use.

1. Scagliotti, G.V., and Novello, S. The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors. Cancer Treat. Rev. 38(4), 292-302 (2012).

2. McKinley, E.T., Bugaj, J.E., Zhao, P., 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. 17(10), 3332-3340 (2011).

3. Buck, E., Gokhale, P.C., Koujak, S., et al. Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer. Mol. Cancer Ther. 9(10), 2652-2664 (2010).

4. Mulvihill, M.J., Cooke, A., Rosenfeld-Franklin, M., et al. Discovery of OSI-906: A selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med. Chem. 1(6), 1153-1171 (2009).