Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases. It transduces cytokine-mediated signals via the JAK-STAT pathway. Four members are in JAK family, they are JAK1, JAK2, JAK3, and TYK2. Specially, JAK1 is involved in many cytokines. Therefore, researchers expect to find out a selective JAK1 inhibitor, effective in inflammatory and immunological diseases. Additionally, Abrocitinib is a potent and selective JAK1 inhibitor, with potent anti-autoimmune disease activity.

In the beginning, Michael L. Vazquez, et al., synthesizes a series of analogues. They possess similar structure, and may have similar function. The researchers find out PF-04965842 (compound 25), the synonym of Abrocitinib is the most promising one.

Then, in the in vitro assay, Abrocitinib exhibits potent inhibitory effect on JAK1, with an IC ₅₀ of 29 nM. Abrocitinib displays much more selectivity at JAK1 over JAK2, and TYK2 (IC₅₀, 803 nM and 1.253 μM, respectively). Abrocitinib inhibits IFNα-stimulated phosphorylation of STAT3. It blocks IFN-stimulated phosphorylation of STAT1 in human whole blood (HWB). Abrocitinib also suppresses pSTAT5 in CD34+ spiked into HWB (JAK2). The IC₅₀s are 189, 163 nM, 7.178 μM, respectively.

Subsequently, in the animal administration, Abrocitinib shows markedly anti-inflammatory activity. In the rat adjuvant-induced arthritis (AIA) disease model, Abrocitinib is dosed QD (once daily) at 5, 15, or 50 mg/kg via oral route. The inhibitor significantly reduces paw swelling. Abrocitinib is orally active, exhibits high bioavailability.

In summary, Abrocitinib is a potent, orally active and highly selective JAK1 inhibitor. It displays significant anti-autoimmune activity. Abrocitinib has become a candidate for the treatment of JAK1-mediated autoimmune diseases. But it still needs more study.

Reference:

J Med Chem. 2018 Feb 8;61(3):1130-1152.