Development of JAK inhibitors for the treatment of immune-mediated diseases: kinase-targeted inhibitors and pseudokinase
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Online ISSN 1976-3786 Print ISSN 0253-6269
REVIEW
Development of JAK inhibitors for the treatment of immune‑mediated diseases: kinase‑targeted inhibitors and pseudokinase‑targeted inhibitors Hyung‑Ook Kim1
Received: 3 September 2020 / Accepted: 29 October 2020 © The Pharmaceutical Society of Korea 2020
Abstract JAKs are a family of intracellular tyrosine kinases consisting of four members, JAK1, JAK2, JAK3, and TYK2. They are key components of the JAK-STAT pathway that transmit signals of many cytokines involved in the pathogenesis of numerous immune-mediated diseases and have been major molecular targets in developing new drugs for the treatment of such diseases. Some small-molecule inhibitors of JAKs have been approved by the FDA for rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease. Now, newer JAK inhibitors with isoformselectivity among the four different JAKs are being developed, with the aim of improving clinical outcomes compared with earlier developed drugs with pan-JAK inhibition. Most of these selective inhibitors target the kinase domains of JAKs, functioning through the traditional inhibition mode of kinases; but recently those that target their pseudokinase domains, allosterically inhibiting the enzymes, have been under development. In this review, key characteristics, efficacy, and safety of FDA-approved and representative drugs in late stages of development are briefly described in order to provide clinical implications with respect to JAK inhibitor selectivity and future development perspectives. The recent development of pseudokinase-targeted inhibitors of JAKs is also included. Keywords Cytokines · Immune-mediated diseases · JAKSTAT pathway · JAK inhibitors · Pseudokinase-targeted inhibitors
* Hyung‑Ook Kim [email protected] 1
Department of Clinical Medicinal Sciences, Konyang University, 121 Daehakro, 32992 Nonsan, Republic of Korea
Introduction Cytokines play crucial roles in the regulation of immune responses and are also key drivers in the pathogenesis of immune-mediated diseases. Targeting them has been a major therapeutic approach for the treatment of such diseases (Liu et al. 2013; Jamilloux et al. 2019). Cytokines are categorized according to the type of their binding receptors. Many of them involved in the pathogenesis of immune-mediated diseases bind to type I/II cytokine receptors. These types of receptors use the same mechanism of signal transduction, called the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway (O’Shea et al. 2013b). Binding of cytokines to their receptors leads to activation of intracellular receptor-associated JAKs followed by phosphorylation of multiple substrates including STATs. Phosphorylated STATs dimerize and translocate into the nucleus where they undertake DNA binding and activate transcription of new cytokines and other target genes (Kontzias et al. 2012; Liongue et al. 2016). Because of the major roles of the JAK-STAT pathway in mediating the effect of cytokines in immunoregulation a
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