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Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.

Original publication

DOI

10.1073/pnas.1501956112

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

10/08/2015

Volume

112

Pages

10768 - 10773

Addresses

Botnar Research Institute, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford OX3 7LD, United Kingdom;

Keywords

CD4-Positive T-Lymphocytes, Cells, Cultured, Humans, Arthritis, Psoriatic, Spondylitis, Ankylosing, Azepines, Triazoles, Isoxazoles, Benzimidazoles, Recombinant Proteins, Immunosuppressive Agents, Interleukin-17, Calorimetry, Crystallography, X-Ray, Drug Evaluation, Preclinical, Gene Expression Regulation, Molecular Structure, Protein Conformation, Protein Structure, Tertiary, Structure-Activity Relationship, Kinetics, Models, Molecular, Adult, Aged, Middle Aged, Female, Male, p300-CBP Transcription Factors, Th17 Cells