Chapter 14 Recent Progress in the Development of Small Molecule Inhibitors of Insulin-Like Growth Factor-1 Receptor Kinase

Publisher Summary This chapter focuses on the most recent advances in small molecule inhibitor design and specifically highlights those inhibitors that are entering the early stages of clinical development. The small molecule inhibitors of insulin-like growth factor-1receptor (IGF-1R) fall into two sub-categories: those that target the ATP-binding pocket of IGF-1R kinase (ATP-competitive) and those that target the substrate-binding site (non ATP-competitive). The most advanced small molecules are ATP-competitive kinase inhibitors. However, the greatest challenge for ATP-competitive inhibitors is achieving selectivity versus other kinases, including the closely related insulin receptor (IR) which shares high overall sequence homology and complete homology among the residues that contact ATP in the kinase-binding domain. In addition, it is interesting to follow the clinical development of molecules, such as AXL-1717, BMS-754807, INSM-18, OSI-906, and XL-228, with respect to efficacy, safety, and tolerability. The hope remains that small molecule inhibitors can provide a complementary approach to mAb therapeutics in terms of efficacy and dosing flexibility, particularly in combination studies with cytotoxics and epidermal growth factor receptor (EGFR) antagonists.