Preclinical characterization of OSI-906: A novel IGF-1R kinase inhibitor in clinical trials

C192 Activation of the insulin-like growth factor-I receptor (IGF-1R) pathway plays an important role in tumor cell proliferation and survival. IGF-1R can also protect tumor cells from a variety of anti-cancer agents, providing a rationale for combination therapy with an IGF-1R inhibitor. We previously reported a research proof-of-concept small molecule IGF-1R kinase inhibitor, cis -3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) and its properties in preclinical models. Here we present the IGF-1R kinase inhibitor OSI-906 that is currently in phase I clinical trials. OSI-906 displayed a cellular IC 50 of 24 nM for inhibition of ligand-dependent IGF-1R autophosphorylation. It had minimal activity against a panel of 47 other protein kinases tested with the exception of the highly homologous insulin receptor. In cellular autophosphorylation assays, OSI-906 exhibited 9-fold selectivity for human IGF-1R (3T3/huIGF1R cells) vs. human insulin receptor (primary hepatocytes). OSI-906 also abolished IGF-induced activation of downstream pAKT, pERK1/2 and p-p70S6K pathways in an IGF-1R transfected 3T3/huIGF1R cell line. Robust anti-tumor efficacy was achieved in this IGF-1R-dependent xenograft model when OSI-906 was administrated orally once a day at doses of 25 and 75 mg/kg. OSI-906 also reduced proliferation and/or survival of a broad panel of tumor cell lines comprised of NSCLC, CRC, pancreatic and breast cancer lines. In addition to single agent activity, combination of OSI-906 with the EGFR inhibitor erlotinib was also investigated. In GEO and HT-29 human colorectal cancer cell lines, EGFR primarily promoted MAPK activation whereas IGF-1R mainly activated the AKT pathway. Simultaneous treatment with OSI-906 and erlotinib effectively blocked both pERK1/2 and pAKT and fully inhibited downstream p-p70S6K, which resulted in synergistic inhibition of cell proliferation and survival in GEO and HT-29 cells in vitro . Similarly, more complete inhibition of pAKT and pERK1/2 signals with the combination was observed in GEO xenograft tumors and corresponded to improved tumor regressions in mice treated with the combination of erlotinib (100 mg/kg/day, po) and low dose (15 mg/kg/day, po) OSI-906 as compared with either agent alone. These preclinical data support clinical development of OSI-906 for treatment of human cancers as a single agent and in combination with other molecular targeted agents including erlotinib.