First-in-class PDE4D bifunctional degraders for inflammatory skin diseases

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by erythema and pruritis, affecting over 15 million people in the US. Th2/Th17 cytokines play key role AD pathogenesis, resulting an increased response, disrupted barrier, susceptibility to infections allergen sensitization. Phosphodiesterase 4 (PDE4) cyclic 3’,5’-adenosine monophosphate (cAMP)-specific phosphodiesterase its expression elevated patients sustaining highly environment. PDE4 inhibition has been shown effectively suppress proinflammatory clinically validated approaches for several conditions. The current standard of care therapies including inhibitors are linked broad adverse effects due their off-target activities. Utilizing our proprietary PRODEGY discovery platform, we have designed potent selective PDE4D bifunctional degraders. degradation dramatically decreases pro-inflammatory released activated T cells vitro. Additionally, degraded efficiently mice spleens treated with lead degrader dose-dependent manner, no effects. Importantly, degraders do not induce significant known neo-substrates, suggesting high specificity. Taken together, propose introduction more potent, specific, safe as novel therapy diseases, such AD.