The synthesis and characterization of A-928605: A potent inhibitor of the insulin-like growth factor receptor (IGF-IR)

A227 Receptor tyrosine kinases (RTKs) have recently become a validated target for cancer chemotherapy. The clinical successes of agents that inhibit RTKs, such as the following: Bcr-Abl, KDR, and EGFR/ ErbB-2, have revealed that a variety of RTKs can be successfully exploited for cancer treatment. Therefore, the search for additional RTKs has led to the proposal that small-molecule inhibitors of the insulin-like growth factor receptor (IGF-IR) might yield effective anti-cancer agents. A high throughput screen of Abbott’s compound repository revealed that the pyrazolopyrimidine-class of kinase inhibitors possessed moderate potency for IGF-IR. Optimization of this class of compounds afforded a series of compounds that demonstrated IGF-IR kinase inhibitory activity less than 100 nM, which correlated with inhibition of p-IGF-IR in a human pancreatic cell line (MiaPaCa-2). Optimization of this class of compounds yielded A-928605, a potent inhibitor of IGF-IR both on the purified enzyme and intracellular IGF-IR phosphorylation (