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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Ruxolitinib (JakaviTM in the EU, JakafiTM in the US), developed by Novartis after licensing from Incyte, was the first JAK inhibitor to be approved (2011), and this was for the treatment of myelofibrosis. Other JAK/STAT inhibitors have since been developed, but these are mostly for inflammatory diseases. For example, tofacitinib (XeljanzisTM) is used to treat moderate to severe active psoriatic arthritis or rheumatoid arthritis in adults who have failed on methotrexate or related medications. Tofacitinib is sometimes given in combination with methotrexate or other arthritis medicines to treat psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and ulcerative colitis. Other analogues include filgotinib (GLPG0634), which is currently under development by Gilead/Galapagos. The pharmaceutical company Eli Lilly has developed baricitinib (OlumiantTM), which selectively and reversibly inhibits JAK1 and JAK2 and is used to treat rheumatoid arthritis in patients who have had an inadequate response to other anti-rheumatic agents. Finally, AbbVie has developed upadacitinib (RinvoqTM), which, like filgotinib, is a selective and reversible inhibitor of JAK1 and is used mainly for rheumatoid arthritis. However, it has received a black box warning for its potential toxicities. Other examples of agents of this type include oclacitinib (ApoquelTM), used for the control of pruritus associated with allergic dermatitis; peficitinib (SmyrafTM), which mainly inhibits JAK3 and is used for treatment of rheumatoid arthritis; and fedratinib (InrebicTM), a JAK2 inhibitor used for the treatment of primary or secondary myelofibrosis.
Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015–2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Xingrui He, Xiabin Chen, Hancheng Zhang, Tian Xie, Xiang-Yang Ye
Jaks play a pivotal role in modulating immune and inflammatory responses to a variety of cytokines. After binding of cytokines to their corresponding receptors, Jaks are activated to phosphorylate cytokine receptors and subsequently phosphorylate and activate signal transducers and activators of transcription (STAT). In the past many years, scientists have made significant progress in understanding Jak-STAT signaling pathway [2], the relationship between Jaks (particular Jak1–3) alteration and pathogenesis, as well as the development of small molecules inhibitor for therapeutic benefits [3–9]. Indeed, Jaks as therapeutic targets have been validated in many clinical trials. As the result, four drugs of small molecule Jaks inhibitor have been approved and marketed to date. Ruxolitinib (Jakafi®) is a Jak1 and Jak2 dual inhibitor by Incyte/Novartis for the treatment of myelofibrosis [10]. Tofacitinib (Xeljanz®) is a pan-Jak inhibitor by Pfizer for the treatment of patients with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis [11]. Oclacitinib (Apoquel®) is another Jak1 and Jak2 dual inhibitor by Zoetis for the treatment of canine allergic dermatitis in animals [12]. Baricitinib (Olumiant®) is a Jak1 and Jak2 dual inhibitor by Eli Lilly/Incyte for the treatment of RA, atopic dermatitis and systemic lupus erythematosus [13].
Upadacitinib for the treatment of rheumatoid arthritis
Published in Expert Review of Clinical Immunology, 2019
Lina Serhal, Christopher J. Edwards
Jakinibs are part of the group of tsDMARDs and constitute novel oral therapeutic agents that mark the beginning of a new era for RA treatment. They act by inhibiting JAKs, downstream small molecules essential to produce numerous key cytokines involved in RA. The first jakinib approved by U.S. Food and Drug Administration (FDA) was Ruxolitinib (JAK1/2 inhibitor) for myeloproliferative malignancies in 2011. In fact, the first game changing success in the oncology field was Imatinib developed in 2000 for the treatment of chronic myeloid leukemia (CML), blocking the signaling of BCR-ABL, which belongs to the tyrosine kinase superfamily [44]. This is certainly not the first time that cancer drugs have shed light on therapeutic targets of importance for rheumatology. Tofacitinib and then Baricitinib were the next Jakinibs to be approved by the FDA and European Medicine Agency (EMA) as second-line treatment for RA [21,45]. In addition, Oclacitinib has been approved for atopic dermatitis in dogs [46]. Another generation of more selective Jakinibs for RA and other autoimmune disorders are being developed into phase II and III clinical trials with potential reduced adverse event profile without loss of efficacy. We will focus on Upadacitinib as a selective JAK1 inhibitor that appears to be safe and effective for RA in multiple phase III clinical trials.
Successful treatment of atopic dermatitis with the JAK1 inhibitor oclacitinib
Published in Baylor University Medical Center Proceedings, 2018
Isabel M. Haugh, Ian T. Watson, M. Alan Menter
Oclacitinib is a Janus kinase-1 (JAK1) inhibitor approved for the treatment of pruritus secondary to allergic dermatitis and atopic dermatitis in canines. JAK1 plays a role in the expression of interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13) in proinflammatory signaling pathways known to contribute to the pathogenesis of atopic dermatitis.1 Oclacitinib is not currently approved for use in humans. We report the first case of a man in his 70s who demonstrated significant relief of signs and symptoms of atopic dermatitis following self-prescription of this veterinary medication.