Type 4 cyclic nucleotide phosphodiesterase (PDE4) selectively inactivates the second messenger cAMP by hydrolyzing the phosphodiester bond, producing AMP. PDE4 has been reported to play a key regulatory role in Hedgehog signaling downstream of smoothened and, thus, represents a potential therapeutic target for Hedgehog-dependent cancers. Eggmanone is a selective inhibitor of PDE4 (IC50 = 72 nM) that antagonizes the Hedgehog signaling pathway. It demonstrates 40- to 50-fold lower potency at PDE3, PDE10, and PDE11 (IC50s = 3, 3.05, and 4.08 μM, respectively). Inhibition of PDE4 activity via eggmanone was shown to activate localized protein kinase A signaling, which, in turn, regulates Gli processing and translocation.
