Proceedings of the National Academy of Sciences - PNAS, 2015-08, Vol.112 (34), p.10768-10773
2015
Details
- Autor(en) / Beteiligte
- Titel
- CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2015-08, Vol.112 (34), p.10768-10773
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2015
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424, 1091-6490eISSN: 1091-6490DOI: 10.1073/pnas.1501956112Titel-ID: cdi_proquest_miscellaneous_1722171661
- Format
- –
- Schlagworte
- Adult, Aged, Arthritis, Psoriatic - metabolism, Arthritis, Psoriatic - pathology, Autoimmune diseases, Azepines - pharmacology, Benzimidazoles - chemistry, Benzimidazoles - pharmacology, Biological Sciences, Calorimetry, CD4-Positive T-Lymphocytes - drug effects, CD4-Positive T-Lymphocytes - metabolism, Cells, Cultured, Clinical trials, Crystallography, X-Ray, Cytokines, Drug Evaluation, Preclinical, Female, Gene expression, Gene Expression Regulation - drug effects, Humans, Immunosuppressive Agents - chemistry, Immunosuppressive Agents - pharmacology, Interleukin-17 - biosynthesis, Interleukin-17 - genetics, Interleukin-17 - metabolism, Isoxazoles - chemistry, Isoxazoles - pharmacology, Kinetics, Male, Medical treatment, Middle Aged, Models, Molecular, Molecular Structure, Monoclonal antibodies, p300-CBP Transcription Factors - antagonists & inhibitors, Protein Conformation, Protein Structure, Tertiary - drug effects, Recombinant Proteins - metabolism, Spondylitis, Ankylosing - metabolism, Spondylitis, Ankylosing - pathology, Structure-Activity Relationship, T cell receptors, Th17 Cells - drug effects, Th17 Cells - immunology, Triazoles - pharmacology