A PDE4 shortform degrader: a first in isoform‐specific PDE4 inhibition

Although phosphodiesterase 4 (PDE4) inhibitors have reached the clinic, their lack of selectivity for PDE4 enzyme isoforms leads to documented side effects. Building in enzyme selectivity has proved difficult because all PDE4 enzymes share highly conserved catalytic domains. The report by Sin et al. describes a novel approach in which a potent PDE4 proteolysis targeting chimera (PROTAC) selectively promotes the degradation of a small subset of PDE4 isoforms (i.e., "short forms") and impacts inflammatory events regulated by these enzymes. This approach offers unparalleled selectivity, potency, and could represent the dawn of a new pharmacology for selective regulation of cyclic AMP (cAMP) signaling.