Abstract 3605: KW-2450, a novel orally-active dual IGF1R/IR inhibitor: Antitumor effects in vitro and in vivo

Abstract

Abstract KW-2450 is an orally active, multi-kinase inhibitor which inhibits both insulin-like growth factor receptor (IGF-1R) and insulin receptor (IR) with an IC50 of 7.39 nmol/L and 5.64 nmol/L, respectively. KW-2450 also exhibits inhibitory activities (>90% at 100 nmol/L) against several protein tyrosine kinases such as FAK, FLT1, FLT3, JAK2, KDR, TRKA, and Aurora A. KW-2450 inhibited the growth of various types of malignant cells, and the reduction of phosphorylated IGF-1R or IR and their downstream signalling such as phosphorylation of AKT and ERK were observed from 10 to 30 nmol/L in vitro. The PK/PD study of KW-2450 was conducted in a human colon cancer HT-29/GFP xenograft model. The plasma concentrations of KW-2450 were measured by LC/MS/MS method and the phosphorylation status of IGF-1R (P-IGF-1R) and AKT (P-AKT) in tumor tissue were examined by Western blotting. A single oral administration of KW-2450 showed inhibition of P-IGF-1R and P-AKT in tumor tissue in accordance with the increasing plasma concentration and peaked 2 hours after the administration of the drug at doses of 10 to 80 mg/kg. In this model, KW-2450 showed a statistically significant suppression of tumor growth by oral administration at a dose of 40 mg/kg once a day for 14 days. In addition, KW-2450 at a dose of 10 mg/kg showed a potent growth inhibitory activity against a human myeloma KMS-12-BM xenograft model, which is sensitive to the compound in vitro. In mice, KW-2450 induced an increase of plasma glucose levels at 20 mg/kg and higher in a dose-dependent manner. However, the increase in glucose was transient and it returned to normal levels within 2 hours at 20 mg/kg, 4 hours at 40 mg/kg and 8 hours at 80 mg/kg. A similar trend was seen in insulin levels which return to normal levels within 4 hours at 10 mg/kg, 8 hours at 20 and 40 mg/kg, and 24 hours at 80 mg/kg. In summary, these pharmacological studies revealed that KW-2450 could act as a potent and selective dual IGF-1R/IR inhibitor and exert antitumor effects on various types of malignant cells in vitro and in vivo, although this compound shows multi kinase inhibitory activity in a cell free system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3605. doi:10.1158/1538-7445.AM2011-3605