2. Academic Validation
  3. Discovery and Characterization of the Topical Soft JAK Inhibitor CEE321 for Atopic Dermatitis

Discovery and Characterization of the Topical Soft JAK Inhibitor CEE321 for Atopic Dermatitis

  • J Med Chem. 2023 Feb 9;66(3):2161-2168. doi: 10.1021/acs.jmedchem.2c01977.
Gebhard Thoma 1,  Rudolf O Duthaler 1,  Rudolf Waelchli 1,  Alice Hauchard 2,  Sandro Bruno 2,  Ulrike Strittmatter-Keller 2,  Anette Orjuela Leon 2,  Sabine Viebrock 2,  Reiner Aichholz 3,  Karen Beltz 3,  Kerri Grove 4,  Shaila Hoque 4,  Patrick J Rudewicz 4,  Hans-Guenter Zerwes 2
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • 2 Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • 3 PK Sciences, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
  • 4 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.
PMID: 36657024 DOI: 10.1021/acs.jmedchem.2c01977
Abstract

The JAK kinases JAK1, JAK2, JAK3, and Tyk2 play key roles in cytokine signaling. Activation of the JAK/STAT pathways is linked to many diseases involving the immune system, including atopic dermatitis. As systemic JAK Inhibitor pharmacology is associated with side effects, topical administration to the skin has been considered to locally restrict the site of action. Several orally bioavailable JAK inhibitors repurposed for topical use have been recently approved or are in clinical development. Here, we disclose our clinical candidate CEE321, which is a potent pan JAK Inhibitor in Enzyme and cellular assays. In contrast to repurposed oral drugs, CEE321 does not display high potency in blood and has a high clearance in vivo. Therefore, we consider CEE321 to be a "soft drug". When applied topically to human skin that was stimulated with the cytokines IL4 and IL13 ex vivo, CEE321 potently inhibited biomarkers relevant to atopic dermatitis.

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