SMART Drug Design: Novel Phosphopeptide and ATP Mimetic-Based Small Molecule Inhibitors of the Oncogenic Protein Kinase pp60 src (Src)

Over the past two decades, the oncogenic protein kinase pp60src (Src) has been the focus of tremendous biological investigations that have identified it to be a promising therapeutic target for both cancer and bone disease drug discovery. The molecular, cellular and in vivo functional properties of Src provide a detailed framework for strategies to advance small molecule inhibitors relative to both its noncatalytic (e.g., SH2) and catalytic (i.e., kinase) domains. This chapter illustrates phoshopeptide mimetic-based small molecule Src SH2 inhibitors and ATP mimetic-based, small molecule Src kinase inhibitors. Key lead compounds exemplifying Src SH2 and Src kinase inhibitors are described with respect to structural biology, drug design and biological activity (in vitro and in vivo). The term SMART refers to small molecule ARIAD therapeutics that has been particularly focused on generating and optimizing novel lead compounds such as AP22408 and AP23464. AP22408 is a prototype bone-targeted Src SH2 inhibitor that blocks binding to phosphorylated ligands and was first to achieve in vivo proof-of-concept in a bone disease model. AP23451 is a second-generation, bone-targeted Src inhibitor and determined to be effective in both osteolytic bone metastasis and osteoporosis in vivo models. AP23464 is a prototype Src kinase inhibitor that is competitive to ATP and is extraordinarily potent in vitro and provides proof-of-concept in Src-dependent, cell assays representing both bone degrading osteoclasts and cancer cells. X-ray crystallographic structures of the aforementioned Src SH2 and Src kinase inhibitors provide insight to SMART drug design strategies. Second-generation Src kinase inhibitors are amidst preclinical and clinical drug development, and such small molecules illustrate varying template classes.