ADT-094

**ADT-094** is a novel small molecule derivative of sulindac, chemically engineered to lack cyclooxygenase (COX-1 and COX-2) inhibitory activity but to possess improved potency as a **dual inhibitor of phosphodiesterase 5 (PDE5) and phosphodiesterase 10 (PDE10)**. Its anticancer mechanism is linked to the inhibition of both PDE5 and PDE10, resulting in selective activation of cyclic GMP (cGMP)-dependent protein kinase G (PKG) signaling, which increases cGMP levels and VASP phosphorylation in cancer cells. This induces apoptotic cell death and suppresses β-catenin/Tcf-mediated transcriptional activity by promoting the phosphorylation, ubiquitination, and proteasomal degradation of β-catenin. ADT-094 demonstrates high tumor selectivity, potently inhibiting colon cancer cell growth at submicromolar concentrations while sparing normal colonocytes. It represents a prototype for a new class of anticancer agents targeting cGMP-degrading PDE isozymes and is under preclinical development for colorectal and potentially other cancers[1][3][5][7][13].