Translating JAKs to Jakinibs

Abstract

The discovery of JAKs and STATs and their roles in cytokine and IFN action represented a significant basic advance and a new paradigm in cell signaling. This was quickly followed by discoveries pointing to their essential functions, including identification of JAK3 mutations as a cause of SCID. This and other findings predicted the use of therapeutically targeting JAKs as a new strategy for treating immune and inflammatory diseases. This now is a reality with seven approved jakinibs being used to treat multiple forms of arthritis, inflammatory bowel disease and myeloproliferative neoplasms, and numerous ongoing clinical trials in other settings. This story provides interesting insights into the process of translating basic discoveries and also reveals the need to return to basic work to fill gaps that now become apparent.

Successful management of familial hemophagocytic lymphohistiocytosis by the JAK 1/2 inhibitor ruxolitinib

“…18 Moreover, other cytokines besides IFN-γ contribute to the pathogene- sis of the disease. 19 Through its capacity to neutralize a broader array of cytokines (IFN-γ, interleukin [IL]-2, and IL-6), 20 ruxolitinib could be more effective to control FHL, as suggested by the case described here.…”

Inhibition of CUB and sushi multiple domains 1 (CSMD1) expression by miRNA-190a-3p enhances hypertrophic scar-derived fibroblast migration in vitro

“…The inhibitors targeting JAKs (Jakinibs) were used as a therapeutic strategy for immune and inflammatory diseases [ 35 , 36 ]. Numerous clinical trials have been conducted and the selective Jakinibs had already been produced and studied in various diseases [ 36 ].…”

“…The inhibitors targeting JAKs (Jakinibs) were used as a therapeutic strategy for immune and inflammatory diseases [ 35 , 36 ]. Numerous clinical trials have been conducted and the selective Jakinibs had already been produced and studied in various diseases [ 36 ]. Oral JAK1 selective inhibitors, upadacitinib and filgotinib, were both reported to exert positive effect on active rheumatoid arthritis patients [ 37 , 38 ].…”

Harnessing Type I IFN Immunity Against SARS-CoV-2 with Early Administration of IFN-β

“…Several classes of drugs interfere with the type I IFN pathways, including antagonists/monoclonal antibodies targeting IFNAR/IFN. Janus kinase (JAK) inhibitors (Jakinibs) target many signaling pathways, depending on their selectivity [ 63 ]. Ruxolitinib inhibits JAK1 and JAK2 and thereby interferes with, respectively, the common cytokine receptor γ -chain (used by IL-2, IL-4, IL-7, IL-9, IL-15); the gp130 pathway (IL-6, IL-11, OSM, LIF); the class II cytokine receptor family (IFN-α/β, IFN-γ, IL-10) (JAK1); and the EPO, TPO, IFNγ, and βc family (IL-3, IL-5, GM-CSF) (JAK2).…”