Identification of small molecule activators targeting TYK2 pseudokinase domain
Tyrosine kinase 2 (TYK2) plays a crucial role in both adaptive and innate immune responses. The catalytic activity of the TYK2 JH1 kinase domain is controlled by the TYK2 JH2 pseudokinase domain and stabilized to maintain its inactive state until the upstream receptor activations. Here, we report the discovery of aminopyridine analogs as novel TYK2 activators through structural modification of a known JH2 binder. Compound 16b demonstrated a dose-dependent increase in TYK2 enzymatic activity.
Authors
- Masaaki Sawa (ORCID: https://orcid.org/0000-0002-0077-2188)
- Takayoshi Kinoshita (ORCID: https://orcid.org/0000-0003-2850-5409)
- Hiroki Taniguchi (ORCID: https://orcid.org/0000-0002-2898-7834)
- Yu Nishioka
- Tien-Cheng Wang
- Hirokazu Matsumoto (ORCID: https://orcid.org/0000-0003-1262-0883)
- Mariko Hatakeyama
Institutions
- Caribbean Research and Management of Biodiversity Foundation (CW)
- Tokyo Metropolitan University (JP)
Publication Details
- Journal
- Bioorganic & Medicinal Chemistry Letters
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1016/j.bmcl.2025.130233
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.00