Small Molecules Engage Hot Spots through Cooperative Binding To Inhibit a Tight Protein–Protein Interaction

摘要: Protein–protein interactions drive every aspect of cell signaling, yet only a few small-molecule inhibitors these exist. Despite our ability to identify critical residues known as hot spots, little is about how effectively engage them disrupt protein–protein interactions. Here, we take advantage the ease preparation and stability pyrrolinone 1, inhibitor tight interaction between urokinase receptor (uPAR) its binding partner, urokinase-type plasminogen activator uPA, synthesize more than 40 derivatives explore their effect on interaction. We report crystal structure uPAR bound previously discovered pyrazole 3 12. While both 12 bind compete with fluorescently labeled peptide probe, inhibit full uPAR·uPA Compounds mimic different hot-spot uPA uPAR, respectively. Interestingly, i...