Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

Omar, Faisa and Findlay, Jane E. and Carfray, Gemma and Allcock, Robert W. and Jiang, Zhong and Moore, Caitlin and Muir, Amy L. and Lannoy, Morgane and Fertig, Bracy A. and Mai, Deborah and Day, Jonathan P. and Bolger, Graeme and Baillie, George S. and Schwiebert, Erik and Klussmann, Enno and Pyne, Nigel J. and Ong, Albert C.M. and Bowers, Keith and Adam, Julia M. and Adams, David R. and Houslay, Miles D. and Henderson, David J. P. (2019) Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases. Proceedings of the National Academy of Sciences of the United States of America, 116 (27). pp. 13320-13329. ISSN 0027-8424

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    Abstract

    Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased V max with unchanged K m), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.