Identification of TYK2 activators. Part 2: Optimization of terminal alkyne substituents to enhance activation potency

  • Bioorg Med Chem Lett. 2026 Nov:140:130728. doi: 10.1016/j.bmcl.2026.130728.
Hirokazu Matsumoto  1 ,  Tien-Cheng Wang  2 ,  Fumio Nakajima  2 ,  Haruka Taniguchi  2 ,  Takayoshi Kinoshita  3 ,  Masaaki Sawa  2
Affiliations
  • 1. Drug Discovery Unit, Carna Biosciences, Inc., Kobe 650-0047, Japan. Electronic address: [email protected].
  • 2. Drug Discovery Unit, Carna Biosciences, Inc., Kobe 650-0047, Japan.
  • 3. Graduate School of Drug Discovery Sciences, Osaka Metropolitan University, Osaka 599-8570, Japan.
PMID: 42413629 DOI: 10.1016/j.bmcl.2026.130728
Abstract

Tyrosine kinase 2 (Tyk2) plays a key role in immune signaling, and its inhibition has been clinically validated for autoimmune diseases. Conversely, activation of Tyk2 is expected to enhance antitumor immunity, representing a novel therapeutic strategy in Cancer Immunotherapy. In our previous study, we identified compound 2, an alkyne-containing derivative, as a novel Tyk2 activator through a scaffold-repurposing design strategy based on a known Tyk2 Inhibitor that binds to the JH2 pseudokinase domain. Here, we expanded our SAR study to explore substituents at the terminal alkyne position based on JH2-domain docking study results. We found the phenylalkyne analog 6g was the most potent activator, with an EC50 of 0.21 μM and a maximal activation effect (Emax) of 7.8-fold.

Keywords
Activator; Pseudokinase domain; Structure activity relationship; TYK2.
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