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  • Review Article
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Kinase inhibition in autoimmunity and inflammation

Nature Reviews Drug Discovery volume 20, pages 39–63 (2021)Cite this article

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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.

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Fig. 1: Current landscape of major druggable inflammatory receptors and corresponding kinases implicated in human disease.
Fig. 2: JAK1, JAK2, JAK3 and TYK2 integrate the signalling cascades of a diverse set of cytokine and growth receptors.
Fig. 3: IRAK4 is the upstream kinase that transduces TLRs and IL-1R signals.
Fig. 4: RIP kinases regulate cell death and inflammatory pathways.
Fig. 5: ITK and BTK in antigen receptor, TLR and FcR signalling.
Fig. 6: TPL2 regulatory inflammatory response downstream of TLRs, TNFR and IL-1R.
Fig. 7: IKKε and TBK1 kinases integrate signalling from nucleic acid sensors.
Fig. 8: Multiple immune receptors trigger NF-κB canonical and non-canonical pathways.

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Acknowledgements

The authors thank Allison Bruce for superb graphic design and figure illustrations.

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Authors and Affiliations

  1. Discovery Department, TRex Bio, South San Francisco, CA, USA

    Ali A. Zarrin

  2. Early Discovery Biochemistry Department, Genentech, South San Francisco, CA, USA

    Katherine Bao & Domagoj Vucic

  3. Protein Science Group, Synthekine, Menlo Park, CA, USA

    Patrick Lupardus

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  1. Ali A. Zarrin
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  2. Katherine Bao
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  3. Patrick Lupardus
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Contributions

A.A.Z. conceived the review topic with major contributions to writing and revisions of the entire manuscript. K.B. contributed to IRAK4, Syk, p38 sections and revisions. D.V. contributed to RIPK section and revisions. P.L. contributed to Table 1.

Corresponding author

Correspondence to Ali A. Zarrin.

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Competing interests

A.A.Z. is an employee of TRexBio and holds stock in TRexBio and the Roche Group. K.B. is an employee of Genentech. P.L. is an employee of Synthekine and holds stock in Synthekine and the Roche Group. D.V. is an employee of Genentech and holds stock and options in the Roche Group.

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Glossary

Rheumatoid arthritis

(RA). A progressive autoimmune and inflammatory disease manifested by joint pain and swelling in the feet and hands that can cause permanent joint destruction and deformity.

Inflammatory bowel disease

(IBD). A group of disorders that involve chronic inflammation of the digestive tract, including ulcerative colitis and Crohn’s disease.

Crohn’s disease

An inflammatory disease that causes inflammation of the lining of the digestive tract, which often spreads deep into affected tissues.

Ulcerative colitis

An inflammatory disease that causes inflammation and sores (ulcers) in the innermost lining of the colon and rectum.

Chronic obstructive pulmonary disease

(COPD). A chronic inflammatory lung disease that causes obstructed airflow from the lungs accompanied by breathing difficulty, cough, mucus production and wheezing.

Idiopathic pulmonary fibrosis

(IPF). A chronic and progressive fibrotic lung disease with unknown aetiology accompanied by scarring, resulting in persistent dry, hacking cough.

Hypoxaemia

An abnormally low concentration of oxygen in the blood.

Plasmacytoid dendritic cells

(pDCs). Specialized, immunomodulatory dendritic cells that produce large quantities of type I interferons in response to viral antigens, with limited capacity to present such antigens to T cells.

Autoantibodies

Antibodies reactive against an individual’s own tissues or organs.

Breakthrough designation

A process designed to expedite the development and review of drugs that are intended to treat a serious condition and for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant end point(s).

Pseudokinase domain

A kinase-like domain that lacks at least one of the conserved catalytic residues.

Death domain

A protein domain that contains six α-helices that facilitate interactions with death domains in other proteins in multisubunit complex formation.

Pyogenic bacterial infections

A condition characteristic of primary immunodeficiency due to myeloid differentiation primary response 88 deficiency in which patients have increased susceptibility to infections owing to their inability to signal through Toll-like receptors to activate inflammation.

X-linked agammaglobulinaemia

A genetic immunosuppressive condition that results in a severe reduction in the number of B cells and, thereby, in the production of protective antibodies. Patients with this condition are predominantly males and are at greater risk of recurrent opportunistic infections.

Pemphigus

Skin disorders that cause blisters or pus-filled bumps. Lesions can also form in the mucus membranes (soft linings of the eyes, nose, mouth, throat and genitals).

American College of Rheumatology 20%

A standard criterion to measure the effectiveness of various arthritis medications or treatments. It means a 20% improvement in tender or swollen joint counts and other parameters.

Tachyphylaxis

A rapidly diminishing response to successive doses of a drug, rendering it less effective. The effect is common with drugs acting on the nervous system.

Amyotrophic lateral sclerosis

A disease of the central nervous system that affects nerves in the brain and spinal cord, causing the progressive loss of muscle control.

Combined immunodeficiency syndrome

Rare disorders caused by mutations in different genes involved in the development and function of B cells and T cells.

Peyer’s patches

Lymphoid nodules located on the outer lining of the small intestine, serving as monitors of the intestinal contents, often bacteria of the microbiome, to prevent the outgrowth of pathogenic bacteria in the gut.

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Zarrin, A.A., Bao, K., Lupardus, P. et al. Kinase inhibition in autoimmunity and inflammation. Nat Rev Drug Discov 20, 39–63 (2021). https://doi.org/10.1038/s41573-020-0082-8

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