Chapter 4: The Discovery of OSI-906, a Small-molecule Inhibitor of the Insulin-like Growth Factor-1 and Insulin Receptors

The insulin-like growth factor-1 and insulin receptors (IGF-1R and IR, respectively) are closely related transmembrane receptor tyrosine kinases. Both receptors have been implicated in the promotion of growth and survival of human tumor cells and therefore have become attractive targets for anti-cancer drug discovery. Herein, we describe the path leading to the discovery and development of OSI-906, a selective, orally bioavailable, low molecular weight dual inhibitor of IGF-1R and IR with demonstrated in vivo efficacy in xenograft models. This discovery was enabled through the use of rational, structure-based drug design to optimize both the binding affinity for IGF-1R/IR and achieve a high degree of selectivity versus other kinases. Emperical medicinal chemistry in combination with high speed analoging synthetic strategies were utilized to expedite the optimization process. Finally, a streamlined testing cascade of in vitro and in vivo IGF-1R and IR models were used to assess for pharmacokinetics, pharmacodynamics, efficacy and safety as well as to enable structure-activity development, compound stratification and optimization. Finally, biomarker and combinatorial drug strategies were applied to facilitate a clinical development plan for this agent.