Targeting PDEs: Realizing the Therapeutic Potential

The 2018 Gordon Research Conference on Cyclic-Nucleotide Phosphodiesterases (PDEs) will focus on efforts to develop the therapeutic potential of phosphodiesterase modulators while also highlighting new biology relevant to the PDEs. As the sole means for terminating the intracellular signals carried by ubiquitous second messengers cAMP and cGMP, the PDEs are uniquely positioned to regulate a host of signaling cascades involved in cell to cell communication, metabolism and gene regulation. Unique elements of the quaternary structure of each family has allowed for the generation of selective inhibitors despite the high level of sequence identity in the active site of the enzymes. Only two families, PDE 6 and 11, still await the development of useful preclinical tools/inhibitors and drug candidates are in or nearing human studies for PDE 1, 2,3,4,5, 9 and 10. Clinical data is accumulating on the effects of PDE 3, 4, 5, 9 and 10 inhibition although only the effects of PDE5 inhibition have been subject to extensive, albeit poorly undocumented, profiling.

The identification of the PDE isoforms and cyclic nucleotide pools regulating specific cellular functions can enable hypothesis driven experimentation about both disease pathophysiology and its potential treatment. With this in mind, the 2018 GRC meeting has been organized along therapeutic areas with sessions devoted to cardiovascular disease, oncology, and metabolic diseases as well as both psychiatry and neurodegeneration. In addition, the use of PDE inhibitors as anti-inflammatory agents will be explored by speakers in several of the sessions. Each session will feature specific research examples of the use of chemical tools in defining potential therapeutic application of PDE modulators. The intervening discussions will bridge these observations to other elements of cyclic nucleotide signaling and regulation with the goal of fostering new, testable ideas.