Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

Abstract

Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, inteferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines’ signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3’-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF-kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies.

The role of oclacitinib in the management of ischaemic dermatopathy in four dogs

“…JAKinibs exert broad anti‐inflammatory and immunosuppressive effects via their blunting of cytokine receptor‐triggered intracellular signalling cascades and downstream gene transcription. In humans, JAKinibs are currently approved for the treatment of rheumatoid arthritis, psoriasis and psoriatic arthritis, myelofibrosis and polycythaemia vera . There are additional reports of the effective off‐label use of JAKinibs for immune‐mediated and autoimmune conditions that include dermatomyositis, alopecia areata and systemic lupus erythematosus …”

Comparing biologicals and small molecule drug therapies for chronic respiratory diseases: An EAACI Taskforce on Immunopharmacology position paper

“…In this area, increasing understanding of the human kinome—the full complement of human protein kinases—particularly its activation in structural and immune cells within the airway of patients with COPD or severe asthma, is keenly needed . Together with formulation for the inhaled route, it will enable the delivery of safe and effective inhibitors with powerful anti‐inflammatory properties that circumvent systemic side effects …”

“…Along with the success of biologicals for treating allergic‐ and other immune‐mediated conditions—such as severe asthma, systemic lupus erythematosus, rheumatoid arthritis, and cancer—small molecule drug (SMD)‐based therapies represent an active field in drug research and development and remain highly sought‐after in immune‐mediated diseases . These two drug classes have powerful and distinct biochemical, pharmacological, and clinically effective characteristics as well as features limiting their therapeutic performance and they can be used together to create powerful combinations .…”

JAK/STAT signaling in regulation of innate lymphoid cells: The gods before the guardians

“…Led by the development of drugs used in the treatment of cancer, targeting of phosphotransferases like the JAKs has become a reality and JAK inhibitors are now used to treat immune‐mediated disorders . First‐generation JAK inhibitors block the enzymatic activity of all the JAKs with various degrees of specificity (Figure ).…”

“…A group of genetically inherited diseases characterized by overproduction of interferons (also known as interferonopathies) has also been treated with JAK inhibitors with positive results . Moreover, JAK inhibitors are being investigated in late phase clinical trials for several other pathologies including alopecia, vitiligo, psoriasis, inflammatory bowel disease, and atopic dermatitis …”