CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses.
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.
Botnar Research Institute, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford OX3 7LD, United Kingdom;
Ariane
A
Hammitzsch
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom;
Cynthia
C
Tallant
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom;
Oleg
O
Fedorov
BioSeek Division of DiscoveRx Corporation, South San Francisco, CA 94080;
Alison
A
O'Mahony
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom;
Paul E
PE
Brennan
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
Duncan A
DA
Hay
Botnar Research Institute, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford OX3 7LD, United Kingdom;
Fernando O
FO
Martinez
Botnar Research Institute, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford OX3 7LD, United Kingdom;
M Hussein
MH
Al-Mossawi
Botnar Research Institute, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford OX3 7LD, United Kingdom;
Jelle
J
de Wit
Botnar Research Institute, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford OX3 7LD, United Kingdom;
Matteo
M
Vecellio
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
Christopher
C
Wells
Botnar Research Institute, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford OX3 7LD, United Kingdom;
Paul
P
Wordsworth
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom;
Susanne
S
Müller
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom; Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, 60438 Frankfurt am Main, Germany paul.bowness@ndorms.ox.ac.uk knapp@pharmchem.uni-frankfurt.de.
Stefan
S
Knapp
Botnar Research Institute, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford OX3 7LD, United Kingdom; paul.bowness@ndorms.ox.ac.uk knapp@pharmchem.uni-frankfurt.de.
Paul
P
Bowness
D000328:Adult; D000368:Aged; D015535:Arthritis, Psoriatic / Q000378:metabolism / Q000473:pathology; D001381:Azepines / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002151:Calorimetry; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D013167:Spondylitis, Ankylosing / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D014230:Triazoles / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors*
C561695:(+)-JQ1 compound; D001381:Azepines; D001562:Benzimidazoles; C000603860:CBP30 compound; C508717:IL17A protein, human; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D007555:Isoxazoles; D011994:Recombinant Proteins; D014230:Triazoles; D050880:p300-CBP Transcription Factors
CBP/p300; Th17; ankylosing spondylitis; bromodomain; epigenetic inhibitors