Discovery of a potent and subtype-selective TYK2 degrader based on an allosteric TYK2 inhibitor.
Bioorg Med Chem Lett
; 79: 129083, 2023 01 01.
Article
em En
| MEDLINE
| ID: mdl-36414177
ABSTRACT
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
TYK2 Quinase
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article