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The insulin-like growth factor-I receptor (IGF-IR) signaling pathway is activated in various tumors, and inhibition of IGF-IR kinase provides a therapeutic opportunity in these patients. GSK1838705A is a small-molecule kinase inhibitor that inhibits IGF-IR and the insulin receptor with IC(50)s of 2.0 and 1.6 nmol/L, respectively. GSK1838705A blocks the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing's sarcoma, and retards the growth of human tumor xenografts in vivo. Despite the inhibitory effect of GSK1838705A on insulin receptor, minimal effects on glucose homeostasis were observed at efficacious doses. GSK1838705A also inhibits the anaplastic lymphoma kinase (ALK), which drives the aberrant growth of anaplastic large-cell lymphomas, some neuroblastomas, and a subset of non-small cell lung cancers. GSK1838705A inhibits ALK, with an IC(50) of 0.5 nmol/L, and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses. GSK1838705A is therefore a promising antitumor agent for therapeutic use in human cancers.

molecular cancer therapeutics

GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers