Selective and potent PROTAC degraders of c-Src kinase

Using dasatinib linked to E3 ligase ligands, we identified a potent and selective dual Csk/c-Src PROTAC degrader. We then replaced dasatinib the c-Src directed ligand with a conformation-selective analog that stabilizes the aC-helix out conformation of c-Src. Using the C-helix out ligand, we identified a PROTAC that is potent and selective for c-Src. Using our c-Src PROTACs, we identified pharmacological advantages to c-Src degradation compared to inhibition with respect to cancer cell proliferation.