Discovery of a potent and subtype-selective TYK2 degrader based on an allosteric TYK2 inhibitor

Tyk2, a member of the JAK family of proximal membrane-bound tyrosine kinases, has emerged as an attractive target for the treatment of autoimmune diseases. Herein, we report the discovery of first-in-class potent and subtype-selective Tyk2 degraders. By conjugating a Tyk2 ligand from a known allosteric Tyk2 Inhibitor with a VHL ligand as the E3 Ligase ligand via alkyl linkers of various lengths, we rapidly identified Tyk2 degrader 5 with moderate Tyk2 degradation activity. Degrader 5 induced Tyk2 degradation without affecting the protein level of subtype kinases (JAK1, JAK2, and JAK3) in Jurkat cellular assays. Furthermore, modifying the Tyk2 ligand moiety of degrader 5 yielded the more potent Tyk2 degrader 37 with retained selectivity for JAKs. Our subtype-selective Tyk2 degraders represent valuable chemical probes for investigating the biology of Tyk2 degradation.

Allosteric TYK2 inhibitor; Degrader; Janus kinase (JAK); Proteolysis-targeting chimera (PROTAC); Tyrosine kinase 2 (TYK2); Von Hippel–Lindau (VHL).