2. Academic Validation
  3. Discovery of a potent and subtype-selective TYK2 degrader based on an allosteric TYK2 inhibitor

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

  • Bioorg Med Chem Lett. 2023 Jan 1;79:129083. doi: 10.1016/j.bmcl.2022.129083.
Jun-Ya Kato 1,  Shigeru Korenaga 2,  Masaru Iwakura 3
Affiliations

Affiliations

  • 1 Synthetic Research Department, ASKA Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: [email protected].
  • 2 Drug Discovery Department, ASKA Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 3 Synthetic Research Department, ASKA Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
PMID: 36414177 DOI: 10.1016/j.bmcl.2022.129083
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.

Keywords

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

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