Selective and Potent PROTAC Degraders of c-Src Kinase
Wuxiang Mao, Nathalie M. Vandecan, C. Raymond Bingham, Pui Ki Tsang, Peter Ulintz, Rachel Sexton, Daniel A. Bochar, Sofía D. Merajver, Matthew B. Soellner
Abstract
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 analogue that stabilizes the αC-helix-out conformation of c-Src. Using the αC-helix-out ligand, we identified a PROTAC that is potent and selective for c-Src. We demonstrated a high degree of catalysis with our c-Src PROTACs. Using our c-Src PROTACs, we identified pharmacological advantages of c-Src degradation compared to inhibition with respect to cancer cell proliferation.
Topics & Concepts
Proto-oncogene tyrosine-protein kinase SrcDasatinibChemistryLigand (biochemistry)Ubiquitin ligaseStereochemistryCell biologyBiochemistryPhosphorylationBiologyUbiquitinSignal transductionReceptorTyrosine kinaseGeneProtein Degradation and InhibitorsUbiquitin and proteasome pathwaysMultiple Myeloma Research and Treatments