Inflammation is driven by a tightly regulated cascade of lipid mediators and enzymatic activity. Human Phospholipase A2 Group V (hPLA2-G5) plays a central role in this process: elevated in inflammatory conditions, it promotes neutrophil and macrophage recruitment and drives the activation of cytosolic phospholipase A2 (cPLA2), leading to arachidonic acid release and PGE2 production - key mediators of chronic inflammation. This makes hPLA2-G5 a promising therapeutic target, particularly in inflammatory pain conditions such as endometriosis, a debilitating disorder characterized by the ectopic growth of endometriotic cells in the abdominal cavity.
 

To explore this target pharmacologically, high-throughput and fragment-based screening identified structurally related small molecule hits, which were further optimized to yield BAY-439, a potent and selective hPLA2-G5 inhibitor with single-digit nanomolar activity. Accepted by the Structural Genomics Consortium as a donated chemical probe, BAY-439 and its inactive counterpart BAY-163 are freely available tools for investigating the role of hPLA2-G5 in both physiological and pathological settings.