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Kinase Inhibition in Autoimmunity and Inflammation

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Kinase Inhibition in Autoimmunity and Inflammation REVIEWS Kinase inhibition in autoimmunity and inflammation Ali A. Zarrin 1 ✉ , Katherine Bao 2, Patrick Lupardus3 and Domagoj Vucic2 Abstract | Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist. One of the main therapeutic approaches to alleviate dysregulated inflammation has been to target the activity of kinases that regulate production of inflammatory mediators. Small- molecule kinase inhibitors have the potential for broad efficacy, convenience and tissue penetrance, and thus often offer important advantages over biologics. However, designing kinase inhibitors with target selectivity and minimal off- target effects can be challenging. Nevertheless, immense progress has been made in advancing kinase inhibitors with desirable drug- like properties into the clinic, including inhibitors of JAKs, IRAK4, RIPKs, BTK, SYK and TPL2. This Review will address the latest discoveries around kinase inhibitors with an emphasis on clinically validated autoimmunity and inflammatory pathways. Rheumatoid arthritis Inflammation is a physiological response of the immune and kinase inhibitors (see below) are effective in treating (RA). A progressive autoimmune system to injury and infection. This process signals the various inflammatory diseases, a large proportion of and inflammatory disease immune system to heal and repair damaged tissue, as patients are not responsive to current therapies, and manifested by joint pain and well as to defend itself against infective agents, such effective treatment approaches for this subset of patients swelling in the feet and hands 4 that can cause permanent joint as viruses and bacteria. However, unresolved or inappro­ are needed . 1 destruction and deformity. priately activated inflammation can become pathogenic . Autoimmune diseases refer to a spectrum of condi­ Chronic inflammation is the primary cause of a broad tions in which the immune system mistakenly attacks Inflammatory bowel disease spectrum of diseases, including rheumatoid arthritis (RA), one’s own body5. This autoimmune response often (IBD). A group of disorders that inflammatory bowel disease (IBD; including gastrointesti­ involves dysregulated adaptive immunity (mediated by involve chronic inflammation Crohn’s disease ulcerative colitis of the digestive tract, including nal conditions such as and ), B and T lymphocytes) towards anatomical self­antigens 5 ulcerative colitis and Crohn’s chronic obstructive pulmonary disease (COPD), asthma, (such as insulin) . Certain human leukocyte antigen disease. psoriasis and idiopathic pulmonary fibrosis (IPF), among (HLA) genes have also been demonstrated to be predic­ others1. Viral and bacterial infections or other insults tive of the development of autoimmune diseases. HLA Crohn’s disease An inflammatory disease that (such toxins, chemicals and so forth) can lead to uncon­ molecules on antigen­ presenting cells present antigens causes inflammation of the trolled acute inflammatory responses and injury often to effector T cells in an interactive process required for lining of the digestive tract, seen in patients with underlying pathogenic conditions antigen-​specific T cell activation. Effector T cells then which often spreads deep (such as COPD or asthma). Acute lung injury (ALI) is a generate local inflammation by producing inflamma­ into affected tissues. syndrome with diagnostic criteria based on hypoxaemia tory cytokines or directly damaging the tissues, whereas + + and a classical radiological appearance, with acute respi­ CD4 CD25 regulatory T (Treg) cells counteract the ratory distress syndrome (ARDS) at the severe end of inflammatory response to maintain immune homeo­ the disease spectrum impairing gas exchange, leading to stasis in tissues. Autoimmune diseases are on the rise 1Discovery Department, multiple organ failure widespread inflammation in the and contribute to approximately 100 clinical indications TRex Bio, South San lungs and sepsis2. A recent example of virally induced affecting 3–5% of the population5. They are caused by Francisco, CA, USA. ALI and ARDS includes SARS­CoV ­2 infection, which is the deregulation of such cellular dynamics resulting in 2Early Discovery associated with a cytokine storm (characterized by high organ damage, including systemic lupus erythema tosus Biochemistry Department, levels of IL­6, IL­12 and IL­1β, and tumour necrosis fac­ (SLE; systemic disease with many organs targeted), Genentech, South San 3 Francisco, CA, USA. tor (TNF)) and defective type I interferon activity . This type 1 diabetes (affecting the pancreas), multiple scle­ inflammatory response resembles the cytokine release rosis (which affects the central nervous system), coeliac 3Protein Science Group, Synthekine, Menlo Park, syndrome observed in patients receiving chimeric disease (which affects the small intestine), primary CA, USA. antigen receptor (CAR) T cell therapy and bispecific biliary cirrhosis (affecting the liver), chronic spontane­ ✉e- mail: [email protected] T cell­ engaging antibodies, which can be treated with ous urticaria (which affects the skin), immune throm­ https://doi.org/10.1038/ anti­ cytokine therapy targeting the IL­6–IL­6 receptor bocytopenic purpura (ITP; platelets), autoimmune s41573-020-0082-8 (IL­6R) signalling pathway3. Although select biologics haemolytic anaemia (which affects red blood cells) and NATURE REVIEWS | DRUG DISCOVERY VOLUME 20 | JANUARY 2021 | 39 REVIEWS • Tocilizumab • Ustekinumab (α-p40) • Sarilumab • Briakinumab (α-p40) • Vobarilizumab (α-IL-6R nanobody) • Guselkumab (α-p19) • Olokizumab (α-IL-6 IgG4) • Tildrakizumab (α-p19) • Clazakizumab (α-IL-6) • NNC01140006 • Risankizumab (α-p19) • Lebrikizumab • Siltuximab (α-IL-6) (α-IL-21) • Emapalumab • Brazikumab (α-p19) (α-IL-13R) • Olamkicept (sgp130Fc) • ATR-107 • AMG 811 (α-IFNγ) • Mirikizumab (α-p19) • AMG 714 • UTTR1147A (IL-22-Fc) • Sifalimumab (α-IFNα) • Dupilumab • Enokizumab • F-652 (IL-22-Fc) • Anifrolumab (α-IFNRα) • Tezepelumab IL-19/IL-20/ IL-13R IL-4R IL-6R IL-9R IL-21R IL-22/IL-23 IFNγ IFNRα/β IL-23R TSLP IL-15R JAK1 JAK2 JAK1 JAK3 JAK1 JAK2 JAK1 JAK3 JAK1 JAK3 TYK2 JAK1 JAK1 JAK2 JAK1 TYK2 TYK2 JAK2 TYK2 JAK2 JAK1 JAK3 JAK2 JAK2 • Tofacitinib (non-selective JAK) • Filgotinib (JAK1) • Fedratinib (JAK2) • Decernotinib (JAK3) • BMS-986165 (TYK2) • Baricitinib (non-selective JAK) • Upadacitinib (JAK1) • PF-06651600 (JAK3 + TECs) • PF-06826647 (TYK2) • Ruxolitinib (non-selective JAK) • Oclacitinib (non-selective JAK) • Anakinra (α-IL-1R) • Rilonacept (IL-1 trap) • Canakinumab (α-IL-1β) • CQ (TLR7/8/9) • IMO-8400 (TLR7/8/9) • Isunakinra (IL-1Rα/ • Rituximab (α-CD20) • SM934 (TLR7/9) • IMO-9200 (TLR7/8/9) • Etokimab (α-IL-33) IL-1β chimeric) • Ocrelizumab (α-CD20) • TAK-242 (α-TLR4) • Eritoran (TLR4/MD2) • MSTT1041A (α-ST2) • Gevokizumab (α-IL-1β) • Obinutuzumab • IMO-3100 (TLR7/9) • REGN3500 (α-IL-33) • Rilonacept (IL-1R-Fc) (glycoeng-α-CD20) • Xolair (α-IgE) TLRs TLR3 ST2 IL-1R BCR FCγR FCεR IRAK4 TBK1/IKKε IRAK4 IRAK4 BTK BTK BTK IRAK1 IRAK1 IRAK1 SYK SYK SYK TBK1 TPL2 TBK1 TPL2 TBK1 TPL2 IKKε IKKε IKKε • Evobrutinib (BTK) • Fostamatinib (SYK) • Branebrutinib (BTK) • GSK2646264 (SYK) • PF-06650833 (IRAK4) • BAY-1834845 (IRAK4) • R835 • GS-4875 • Fenebrutinib (BTK) • Entospletinib (SYK) • BMS-986126 (IRAK4) • CA-4948 (IRAK4) (IRAK4/1) (TPL2) • PRN1008 (BTK) • Iscalimab • Etanercept (TNFR-Fc) • Bleselumab • Belimumab • Adalimumab (α-TNF) • BI-655064 • Infliximab (α-TNF) • Abatacept • Dapirolizumab (α-CD40L) • BION-1301 (α-April) • Cabiralizumab (α-CSF1R) • Golimumab (α-TNF) (CTLA4-Ig) • Letolizumab (α-CD40L) • Denosumab • Atacicep (α-TACI) • AMG-820 (α-CSF1) TNFR TCR CD40 RANKL BAFFR TACI/BCMA CSF1R RIP1 TPL2 ITK RLK NIK NIK NIK NIK CSF1RK RIP3 ERK5 • GSK2982772 • GS-4875 • JTE-051 • PLX-3397 • ABT-869 (RIP1) (TPL2) (ITK) • JNJ-40346527 • BLZ-945 • DNL747 (RIP1) • ARRY-382 40 | JANUARY 2021 | VOLUME 20 www.nature.com/nrd REVIEWS ◀ Fig. 1 | Current landscape of major druggable inflammatory receptors and Kinases (518 encoded in genome) are enzymes that corresponding kinases implicated in human disease. Major inflammatory pathways phosphorylate up to one­third of the proteome, and their and downstream kinases are depicted to show surface versus intracellular drug targets, utility as drugs is expanding in cancer, inflammatory highlighting drugs that are currently being clinically evaluated or already approved. and neurodegenerative diseases9. Owing to the distri­ All biologics that are included have mostly been evaluated in phase II trials and beyond. All small-molecule kinase inhibitors have been evaluated in phase I and beyond. BAFFR, bution of select kinases in multiple signalling cascades B cell activating- factor receptor; BCMA, B cell maturation antigen; BCR, B cell receptor; in immune cells, the use of small­molecule kinase inhibi­ BTK, Bruton’s tyrosine kinase; CD40L, CD40 ligand; CSF1R, colony-stimulating factor 1 tors has the potential to disable inflammation in a tar­ 10 receptor; CTLA4, cytotoxic T lymphocyte- associated protein 4; FcεR, Fcε receptor; IKKε, geted fashion . In addition, emerging data suggest that inhibitor of NF-κ B subunit-ε ; IL-1R, IL-1 receptor; IRAK, IL-1R- associated kinase; ITK, IL-2- combination therapy with non­overlapping therapeutics inducible T cell kinase; JAK, Janus-associated kinase; MD2, myeloid differentiation factor 2; (such as combinations of biologics and kinase inhibitors) NF-κ B, nuclear factor-κ - light- chain- enhancer of activated B cells; NIK, NF- κB- inducing
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