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

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