Current application status and structure-activity relationship of selective and non-selective JAK inhibitors in diseases

Abstract

JAK kinase includes four family members: JAK1, JAK2, JAK3, and TYK2. It forms the JAK-STAT pathway with signal transmitters and activators of subscription (STAT). This pathway is one of the main mechanisms by which many cytokine receptors transduce intracellular signals, it is associated with the occurrence of various immune, inflammatory, and tumor diseases. JAK inhibitors block the signal transduction of the JAK-STAT pathway by targeting JAK kinase. Based on whether they target multiple subtypes of JAK kinase, JAK inhibitors are categorized into pan-JAK inhibitors and selective JAK inhibitors. Compared with pan JAK inhibitors, selective JAK inhibitors are associated with a specific member, thus more targeted in therapy, with improved efficacy and reduced side effects. Currently, a number of JAK inhibitors have been approval for disease treatment. This review summarized the current application status of JAK inhibitors that have been marketed, advances of JAK inhibitors currently in phase Ш clinical trials, and the structure-activity relationship of them, with an intention to provide references for the development of novel JAK inhibitors.

Keywords: Allosteric inhibitors; Covalent inhibitors; JAK inhibitors; JAK-STAT; Selective inhibitors.