In vivo evaluation of OSI-906, a novel small molecule kinase inhibitor of the insulin-like growth factor-1 receptor (IGF-1R)

B244 The insulin-like growth factor-1 receptor (IGF-1R) has emerged as a potentially viable target for the development of novel cancer therapeutics. IGF-1R is primarily activated by its cognate ligands, insulin-like growth factor-1 (IGF-1) and -2 (IGF-2). Ligand binding results in receptor autophosphorylation and stimulation of IRS, leading to the activation of PI-3K/AKT/mTOR and Grb2/Sos/Ras/MAPK signaling pathways that are important for tumor cell survival and growth. IGF ligands are upregulated in several tumor types in which IGF-1R is expressed, providing rationale to investigate this target for the development of a novel anti-cancer therapeutic. Several biologic approaches including antibodies targeting the receptor have been pursued. However, very few small molecule inhibitors interfering with the kinase activity of IGF-1R have advanced to the clinical setting. Here we report the preclinical in vivo pharmacology profile of OSI-906, a potent small molecule kinase inhibitor of IGF-1R that has recently entered Phase I clinical trials. OSI-906 has favorable pharmacokinetic properties including linear exposure in rodents and good oral bioavailability in mice and higher species. In a pharmacodynamic model utilizing the GEO colon carcinoma xenograft, a single oral dose of OSI-906 at 60 mg/kg provided significant target inhibition (80%) for up to 24 hours as measured by loss of phospho-IGF-1R protein in xenograft tumors. The PK/PD profile of OSI-906 correlated to substantial tumor growth inhibition in several xenograft models (GEO, Colo-205, cal-62). As the kinase domains of IGF-1R and insulin receptor are highly homologous we also observed hyperglycemia in association with OSI-906 treatment. A once daily schedule of OSI-906 at 60 mg/kg resulted in transient increases in blood glucose levels. A pharmacodynamic study revealed that while OSI-906 inhibited IGF-1R for 24 hours it only transiently inhibited insulin receptor. This was consistent with modest selectivity of the compound for IGF-1R vs. insulin receptor observed at the cellular level. Moreover, we found that a low BID dose schedule of OSI-906 was able to reduce the hyperglycemia while retaining similar anti-tumor efficacy. These results suggest that alternate dosing schedules may be employed to minimize the potential hyperglycemia effects. In summary, our data suggest that OSI-906 is a novel potent inhibitor of IGF-1R with a promising preclinical pharmacology profile. OSI-906 may have utility in tumor types that are dependent on IGF-1R tyrosine kinase activity. Hence, phase I clinical trials are currently ongoing to investigate its clinical potential.