CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses
Hammitzsch A., Tallant C., Fedorov O., O’Mahony A., Brennan PE., Hay DA., Martinez FO., Al-Mossawi MH., de Wit J., Vecellio M., Wells C., Wordsworth P., Müller S., Knapp S., Bowness P.
Significance Epigenetic inhibitors have shown considerable promise for the treatment of malignant and inflammatory diseases. We present here the detailed characterization of a potent and highly selective inhibitor of the bromodomains of CBP (CREB binding protein)/p300. Functional preclinical data studying cells derived from patients with ankylosing spondylitis and psoriatic arthritis (two human Th17-driven diseases) show that selective inhibition of the CBP/p300 bromodomain with CBP30 strongly reduces secretion of IL-17A, without having the broader and potentially deleterious effects on cytokine production and gene transcription of the pan-BET (bromo and extraterminal domain protein family) inhibitor JQ1. CBP/p300 play a significant role in IL-17A production, and CBP/p300 inhibition is a promising therapeutic strategy in human type-17–mediated diseases such as ankylosing spondylitis and psoriatic arthritis.