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

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.