Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Abstract

In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

“…Interestingly, GWAS performed on other, larger population samples for phenotypes other than TB have shown that homozygosity for TYK2 P1104A has a strong protective effect (ORs ranging from 0.1 to 0.3) against various autoinflammatory or autoimmune conditions (25,(48)(49)(50)(51)(52)(53)(54). In light of these results, the potential pharmacological benefits of TYK2 inhibitors for treating autoinflammatory or autoimmune conditions are currently being evaluated (55)(56)(57). Our findings indicate that if such treatments were to be introduced into widespread use, then it would be important to assess the risk of TB before and during treatment, as is currently done for anti-TNF immunotherapy (58).…”

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis

“…Histopathology was used to confirm imaging observations in the SKG experiments. In our hands, the onset of small intestine kinases (JAKs), are of particular interest given the large number of orally available small-molecule inhibitors developed recently (15). JAK inhibitors (JAKinibs) already are approved for clinical use in rheumatoid arthritis and PsA, and a recent proof-of-concept trial showed that the pan-JAK inhibitor tofacitinib provided both symptomatic control in AS and reduced axial joint inflammation on MRI (16).…”

Il-23/Il-17 Inhibitors in Immunoinflammatory Rheumatic Diseases: New Horizons

“…Расширение представлений о роли оси ИЛ23/ИЛ17 в развитии ИВЗ послужило мощным стимулом для разработки генно-инженерных биологических препаратов (ГИБП) и «малых» молекул, блокирующих эффекты цитокинов оси ИЛ23/ИЛ17 или внутриклеточную сигнализацию этих цитокинов [10,[27][28][29], некоторые из которых уже широко применяются для лечения ИВЗ, а другие проходят стадию клинических или преклинических исследований (табл. 2).…”

“…Большой интерес представляет возможность модуляции оси ИЛ23/ИЛ17 с использованием низкомолекулярных химически синтезированных препаратов (тофацитиниб, барицитиниб и др. ), ингибирующих внутриклеточные «сигнальные» молекулы -JAK (Янус-киназы), так называемые Якинибы (Jakinibs), которые с успехом применяются для лечения РА [27][28][29]. Теоретическим обоснованием их эффективности при псориазе, ПсА, АС и ВЗК является модуляция оси ИЛ23/ИЛ17 за счет блокирования JAK2-TYK2/STAT3-STAT4, JAK1-TYK2-STAT5, участвующих в сигнализации ИЛ12, ИЛ23, ИЛ21, ИЛ22 и, вероятно, других патогенетически значимых для каждого конкретного заболевания воспалительных медиаторов (ИЛ15, ИФНγ и др.)…”