A Decade of JAK Inhibitors: What Have We Learned and What May Be the Future?

Abstract

The discovery of cytokines and their role in immune and inflammatory disease led to the development of a plethora of targeted biologic therapies. Later, efforts to understand mechanisms of cytokine signal transduction led to the discovery of JAKs, which themselves were quickly identified as therapeutic targets. It has been a decade since the first JAK inhibitors (jakinibs) were approved, and there are now 9 jakinibs approved for the treatment of rheumatic, dermatologic, hematologic, and gastrointestinal indications, along with emergency authorization for COVID-19. In this review, we will summarize relevant discoveries that led to first-generation jakinibs and review their efficacy and safety as demonstrated in pivotal clinical studies. We will discuss the next generation of more selective jakinibs, along with agents that target kinase families beyond JAKs. Finally, we will reflect on both the opportunities and challenges ahead as we enter the second decade of the clinical use of jakinibs.

Figure 1:

Type I and type II cytokine receptors associate with different members of the Janus kinase family (JAK1, JAK2, JAK3, and TYK2) in order to transduce intracellular signals. Selective blockade of specific JAK molecules should inhibit specific biologic actions while allowing other JAK-dependent cytokines to signal normally. For example, by selectively inhibiting JAK1, the adverse events related to JAK2 inhibition such as anemia and neutropenia should be avoided. JAK3 mediated signaling, which is associated exclusively with the common γ-chain receptor, should also be unaffected, sparing T, B, and NK (natural killer) cell function. JAK, Janus kinase; TYK, tyrosine kinase; IL, interleukin; EPO, erythropoietin; TPO, thrombopoietin; granulocyte colony-stimulating factor (G-CSF); GM-CSF, granulocyte–macrophage colony-stimulating factor; GH, growth hormone; OSM, oncostatin M; IFN, interferon. Created with BioRender.com

Figure 2:

SARS-CoV-2 entry is mediated by ACE2 (Angiotensin converting enzyme 2), a receptor widely expressed in the lungs, heart, vasculature, kidneys, and gastrointestinal tract. Primary site of infection is alveolar epithelial cells in the lungs, and rapid replication of virus can lead to a hyperimmune response. Macrophage activation and chemokine release for neutrophil, TH1, and NK cell recruitment can lead to a massive cytokine release responsible for the clinical evolution to acute respiratory distress syndrome (ARDS). Jakinibs such as baricitinib can potentially block viral entry by inhibiting numb-associated kinase family (NAK) proteins AAK1 and cyclin G-associated kinase (GAK). During the inflammatory phase, many of the cytokines elevated in Covid-19 (IL-6, IL-12, and IFNγ) signal via JAKs, and therefore, jakinibs are being considered as potential therapeutics in severe SARS-CoV-2. JAK, Janus kinase; TYK, tyrosine kinase; IL, interleukin; MIP, macrophage inflammatory protein; TNF, tumor necrosis factor; IP, interferon γ-induced protein. Created with BioRender.com