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Protein kinases: drug targets for immunological disorders

Nature Reviews Immunology volume 23, pages 787–806 (2023)Cite this article

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An Author Correction to this article was published on 27 November 2023

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Abstract

Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton’s tyrosine kinase inhibitors) targeting antigen receptor signalling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.

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Fig. 1: Major kinase classes and immunoreceptor signalling.
Fig. 2: Timeline of approval of key protein kinase inhibitor drugs for cancer and immune-mediated disease.
Fig. 3: Cytokines and receptor classes, their immunological effects, disease association and corresponding Janus kinase inhibitors.

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Acknowledgements

This work was supported by the US NIH Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute of Allergy and Infectious Diseases. Owing to how fast this field is moving, we apologize for any approvals and clinical trials we may have missed.

Author information

Authors and Affiliations

  1. Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    Leslie Castelo-Soccio

  2. Juvenile Myositis Pathogenesis and Therapeutics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    Hanna Kim

  3. Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    Massimo Gadina

  4. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Pamela L. Schwartzberg

  5. Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK

    Arian Laurence

  6. University College London Hospitals NHS Foundation Trust, London, UK

    Arian Laurence

  7. Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    John J. O’Shea

Authors
  1. Leslie Castelo-Soccio
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  2. Hanna Kim
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  3. Massimo Gadina
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  4. Pamela L. Schwartzberg
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  5. Arian Laurence
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  6. John J. O’Shea
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Contributions

L.C.-S. and H.K. contributed equally. All authors contributed to all aspects of the article.

Corresponding author

Correspondence to Arian Laurence.

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Competing interests

The NIH holds a patent entitled ‘Janus family kinases and identification of immune modulators’ US7070972B1. J.J.O’S. receives income from the US Government for royalties. All other authors have no competing interests.

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Nature Reviews Immunology thanks L. Berg, I. McInnes, A. Najm and A. Zarrin for their contribution to the peer review of this work.

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Glossary

ACR20 response

American College of Rheumatology response to intervention defined as at least 20% improvement in both the tender joint count and swollen joint count and at least 20% improvement in 3–5 other core set measures (such as pain and physical function).

Alopecia areata

(AA). An autoimmune disease of the hair follicle characterized by non-scarring hair loss. Cytotoxic CD8+NKG2D+ T cells and interferon-γ have an important role in its development.

Amyotrophic lateral sclerosis

A severe neurodegenerative disease defined by loss of upper and lower motor neurons with associated accumulation of protein aggregates in cells. There are alterations in T cells, monocytes, complement and cytokines in the peripheral blood of patients with this disease.

Ankylosing spondyloarthritis

A form of arthritis that causes inflammation in the joints and ligaments of the spine and overtime causes the bones to fuse. Males carrying the MHC class I allele HLA-B27 have an increased risk of developing the disease.

Atopic dermatitis

(AD). A chronic pruritic skin condition that is characterized by inflammation, redness and irritation of the skin. It has been associated with increased production of T helper 2 cytokines.

Chronic eosinophilic leukaemia

A myeloproliferative neoplasm of the blood with clonal overproduction of eosinophils in the bone marrow.

Chronic mucocutaneous candidiasis

Hereditary immunodeficiency syndromes associated with chronic non-invasive Candida infection of the skin, nails and mucous membranes owing to dysfunctional T cells.

Chronic myeloid leukaemia

(CML). Indolent cancer with clonal increases in myeloblasts in the bone marrow and blood. It is often marked by a chromosome change called the Philadelphia chromosome, giving rise to the fusion protein BCR–ABL.

Dermatomyositis

An inflammatory disease that leads to chronic muscle inflammation (myositis), muscle weakness and skin rash.

Graft versus host disease

An immune response mounted against the recipient of an allograft by immunocompetent donor T cells that are derived from the graft. Typically, it is seen in the context of allogeneic bone marrow transplantation.

Haemophagocytic lymphohistiocytosis

A severe, life-threatening, systemic inflammatory syndrome characterized by uncontrolled proliferation of activated lymphocytes and macrophages and cytokine storm. Primary forms are caused by genetic variants commonly affecting cytotoxic lymphocyte function. Secondary forms can occur following viral infections, such as Epstein–Barr virus, or cancers, such as leukaemia.

Hidradenitis suppurativa

A painful, chronic relapsing inflammatory skin condition characterized by follicular occlusion, scarring and sinus tracts in apocrine-bearing areas of the skin. Aberrant activation of innate immunity and microbiome dysbiosis contribute to its pathogenesis.

Hypereosinophilic syndrome

A group of blood disorders characterized by sustained overproduction of eosinophils that enter various tissues leading to damage to these organs.

Hyperlipidaemia

A condition in which there are too many lipids such as cholesterol and triglycerides in the blood. Over time, these lipids can become deposited in arteries and increase the risk of blockages.

Idiopathic pulmonary fibrosis

A chronic inflammatory disease of the lungs characterized by scarring, leading to a progressive and irreversible decline in lung function.

Immune thrombocytopenia

A blood disorder of low platelet counts owing to autoimmune activity against platelet antigens, leading to easy bruising and bleeding.

Juvenile idiopathic arthritis

Type of chronic rheumatic disease in children characterized by progressive joint destruction and sometimes systemic inflammation. A complex interaction between lymphocytes, monocytes, macrophages and neutrophils triggers the disease.

Major adverse cardiovascular events

A composite end point classically defined to include myocardial infarction, stroke and cardiovascular death.

mTOR

A conserved protein kinase that regulates cellular metabolism, autophagy, protein translation, cell growth and survival in response to environmental cues. The immunosuppressive drug rapamycin inhibits mTOR complex 1 by binding FKBP12 and is used in allograft transplantation.

Myeloproliferative diseases

Blood cancers caused by changes in bone marrow stem cells. The most common types are chronic myelogenous leukaemia, polycythemia vera, chronic idiopathic myelofibrosis, essential thrombocytopenia and chronic eosinophilic leukaemia.

Psoriatic arthritis

(PsA). A form of arthritis that affects some individuals with psoriasis leading to inflammation of the joints and entheses (sites where tendons and ligaments attach to bone).

Refractory chronic urticaria

Defined by the presence of evanescent wheals, angioedema or both for longer than 6 weeks that is not controlled by higher dose non-sedating H1 antihistamines in combination with other standard therapies.

Scarring alopecia

A group of hair disorders associated with inflammation leading to destruction of the hair follicle and hair loss.

Septic shock

A life-threatening condition in which dangerously low blood pressures occur secondary to an immune reaction to a systemic infection.

Systemic lupus erythematosus

(SLE). A chronic immune disease and most common form of lupus in which there is a breakdown of self-tolerance with activation of autoreactive T and B cells. Widespread inflammation leads to tissue damage and can affect the joints, skin, brain, kidneys and blood vessels.

Systemic mastocytosis

A blood disorder with increased mast cells in the blood, which leads to the release of vasoactive cell mediators. This leads to various symptoms including anaphylaxis, flushing, gastrointestinal and neuropsychiatric complaints.

Systemic sclerosis

A chronic disease characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and internal organs.

Ulcerative colitis

Chronic inflammation of the bowels in which abnormal reactions of both the innate and adaptive immune system cause inflammation and ulcers on the inner lining of the large intestine. Antibodies to resident microbiota highlight influence of B cells, and impact of cytokines leads to sustained inflammation.

Venous thromboembolism

A condition in which a blood clot (thrombus) form in a deep vein, known as venous thrombosis. It can also be associated with or without pulmonary embolism, whereby a thrombus breaks off (embolizes) and flows to the lungs to lodge there.

Vitiligo

A chronic inflammatory condition of the skin in which pigment-producing melanocytes are targeted leading to patches of visible depigmentation. The key immune cells include T helper 1 cells, cytotoxic T cells, regulatory and memory T cells as well as dendritic cells and natural killer cells. Key mediators such as interferon-γ and IL-15 are also implicated in its pathogenesis.

X-linked agammaglobulinaemia

An inherited immune disease caused by an inability to produce B cells or inability of B cells to make immunoglobulins.

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Castelo-Soccio, L., Kim, H., Gadina, M. et al. Protein kinases: drug targets for immunological disorders. Nat Rev Immunol 23, 787–806 (2023). https://doi.org/10.1038/s41577-023-00877-7

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