Discovery of a PDE4B and PDE4D selective bifunctional degrader for management of chronic inflammatory disorders

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by redness and itching, impacting over 15 million individuals in the US. The pathogenesis of AD involves T helper 2 (T_H2) and 17 (T_H17) cytokines, which contribute to increased inflammation, a compromised skin barrier, and heightened susceptibility to infections and allergen sensitization. PDE4, a specific enzyme that degrades cyclic 3',5'-adenosine monophosphate (cAMP), shows elevated expression in AD patients, maintaining a highly inflammatory environment. Inhibiting PDE4 effectively reduces pro-inflammatory cytokines in several chronic inflammatory diseases. However, current PDE4 inhibitors are often associated with significant adverse effects due to off-target activities. Recent developments in targeted protein degradation techniques have prompted interest in alternative strategies to modulate PDE4 activity with improved selectivity. Consequently, we have developed potent and selective bifunctional degraders for PDE4B/D. These degraders significantly reduce pro-inflammatory cytokine release from activated T cells <i>in vitro</i>, demonstrating a potency which is a thousand times greater than traditional PDE4 inhibitors. In addition, the PDE4B/D degrader (BTX-AP02) efficiently degrades PDE4D in the spleens of treated mice in a dose-dependent manner, with no significant adverse effects at dose levels used in the study. We also demonstrate the efficacy of our lead oral PDE4B/D degrader (BTX-AP04) in a mouse model of graft-versus-host disease (GvHD). Notably, our PDE4D degraders exhibit minimal degradation of known neo-substrates of cereblon (CRBN), indicating high specificity. Taken together, we propose the introduction of a more potent, specific, and safe PDE4B/D degrader as a novel treatment for inflammatory skin conditions such as AD.