AI Article Synopsis
- Janus kinases (JAKs) are key enzymes that play a role in managing the body's immune response, inflammation, and blood cell formation by mediating cytokine and growth factor signaling.
- * Researchers focused on developing a selective JAK1 inhibitor to target inflammatory cytokines while sparing other functions regulated by JAK2, starting from the existing drug tofacitinib.
- * Modifications to the chemical structure of tofacitinib led to the discovery of new JAK1 inhibitors, like PF-04965842, which showed strong effectiveness in models of autoimmune disease and have been proposed for clinical trials.
Article Abstract
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
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| http://dx.doi.org/10.1021/acs.jmedchem.7b01598 | DOI Listing |
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