Abstract

The phosphodiesterase 4 (PDE4) enzyme family plays a pivotal role in regulating levels of the second messenger cAMP. Consequently, PDE4 inhibitors have been investigated as a therapeutic strategy to enhance cAMP signaling in a broad range of diseases, including several types of cancers, as well as in various neurologic, dermatological, and inflammatory diseases. Despite their widespread therapeutic potential, the progression of PDE4 inhibitors into the clinic has been hampered because of their related relatively small therapeutic window, which increases the chance of producing adverse side effects. Interestingly, the PDE4 enzyme family consists of several subtypes and isoforms that can be modified post-translationally or can engage in specific protein-protein interactions to yield a variety of conformational states. Inhibition of specific PDE4 subtypes, isoforms, or conformational states may lead to more precise effects and hence improve the safety profile of PDE4 inhibition. In this review, we provide an overview of the variety of PDE4 isoforms and how their activity and inhibition is influenced by post-translational modifications and interactions with partner proteins. Furthermore, we describe the importance of screening potential PDE4 inhibitors in view of different PDE4 subtypes, isoforms, and conformational states rather than testing compounds directed toward a specific PDE4 catalytic domain. Lastly, potential mechanisms underlying PDE4-mediated adverse effects are outlined. In this review, we illustrate that PDE4 inhibitors retain their therapeutic potential in myriad diseases, but target identification should be more precise to establish selective inhibition of disease-affected PDE4 isoforms while avoiding isoforms involved in adverse effects.