JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

Abstract

This corrects the article DOI: 10.1038/nrd.2017.201.

Figure 1:. Signalling by type I and II cytokine receptors.

(A) Type I and II cytokine receptors comprise subunits that physically associate with Janus kinases (JAKs). Type I/II cytokine receptors do not have any enzymatic activity but instead depend upon JAKs to transduce intracellular signals. JAK proteins share 4 components: the kinase domain, the pseudokinase domain, the FERM (Four-point-one protein, Ezrin, Radixin, Moesin) domain, and the SH2-like domain. The canonical JAK/STAT pathway is initiated by extracellular association of cytokines with their cognate receptors (1). This activates the receptor, resulting in apposition of receptor-associated JAKs (2). JAKs are tyrosine kinases, so upon activation they transfer phosphate from ATP to tyrosine residues on other proteins, including cytokine receptors and JAKs themselves. This is an important event, as tyrosine phosphorylation of kinases, including JAKs, triggers their enzymatic activity. Tyrosine phosphorylation of receptors (3) creates docking sites for signaling molecules including signal transducers and activators of transcription (STATs), which also undergo JAK-mediated phosphorylation of their tyrosine residues (4), leading to STAT dimerization, nuclear translocation (5), DNA binding and target gene induction (6). (B). Monoclonal antibodies can block Type I/II cytokines and their receptors. In contrast, jakinibs block cytokine signaling by inhibiting kinase activity. This prevents JAKs from phosphorylating STATs and other substrates, so that intracellular signals cannot be transduced. Because JAKs are critical for multiple different cytokines, jakinibs block the action of a range of cytokines, unlike biologics. First generation jakinibs block multiple JAKs whereas second generation jakinibs may have more selectivity for JAKs and so may inhibit a narrow range of cytokines. Cytokine receptors, JAK and STATs are drawn based on structural information ^,.

Figure 2:. Effects of targeting different JAKs.

Type I and II cytokine receptors physically associate with JAKs, which transduce downstream intracellular signals. Different receptors associate with different JAKs, so that selective blockade of one JAK can inhibit a specific biologic function while allowing other JAK-dependent cytokines to signal normally. For example, selective blockade of JAK3, which is associated exclusively with the common gamma chain receptor, should inhibit T cell, NK cell, and B cell function while leaving hematopoietic and metabolic pathways unaffected. IL, interleukin; IFN, interferon; Jak, Janus kinase; NK, natural killer

Figure 3:. Chemical structure and attributes of various jakinibs

The first-generation JAK inhibitors ruxolitinib, tofacitinib, and baricitinib block multiple JAKs. The newer pan-jakinib peficitinib has IC₅₀ of 3.9, 5.0, 0.71 and 4.8 nmol/L for JAK1, JAK2, JAK3 and TYK2 enzymatic activity respectively. A variety of next-gen JAK inhibitors are emerging. Several block JAKs and other kinases (R333, cerdulatinib, SB-1578), while many are selective for one particular JAK isoform. Filgotinib, Upadacitinib, and Solcitinib block JAK1; Decernotinib and PF-06651600 block JAK3; and BMS986165, NDI-021232, NDI=031407, PF-06700841, and SAR-20347 all block TYK2. Chemical structures and data regarding metabolism/clearance are shown where available. (IC₅₀, inhibitory concentration 50%; CYP, cytochrome P; JAK, Janus kinase)