Structure-based identification and biological evaluation of a novel MAPKAPK2 inhibitor for pancreatic cancer

Pancreatic cancer remains a lethal malignancy with few effective treatment options. MAPKAPK2, a downstream effector of p38 signaling, represents a potential target for disrupting tumor survival pathways. Structure-guided computational screening has become an important strategy for exploring large chemical spaces and prioritizing tractable hits. Therefore, we combined computational and experimental approaches to discover structurally novel MAPKAPK2 inhibitors for pancreatic cancer drug development. Structure-based virtual screening was performed to identify novel MAPKAPK2 inhibitors. Compounds were evaluated by kinase assays, selectivity profiling, and structural similarity analysis. Cellular effects were evaluated primarily in BxPc-3 and Mia PaCa-2 cells, with additional viability and growth analyses performed in Panc-1, AsPc-1, and nonmalignant HPDE6c7 cells. Drug-likeness, docking, and hinge-binding filters reduced approximately 280,000 compounds to experimentally testable hits. Analog expansion from the initial hit 77502 identified the more potent compound 77501, which inhibited MAPKAPK2 with an IC 50 value of 243.1 nM. Importantly, compound 77501 showed high selectivity for MAPKAPK2 over other MAPKAPK family members and across a representative kinase panel, while remaining structurally distinct from known MAPKAPK2 inhibitors. Functionally, 77501 suppressed pancreatic cancer cell growth and migration, induced G2/M arrest and apoptosis, and reduced the phosphorylation of the MAPKAPK2 downstream substrates HSP27 and E2F1. RNA sequencing identified 585 differentially expressed genes, linking MAPKAPK2 inhibition to p53 signaling, endoplasmic reticulum stress, apoptosis activation, and repression of proliferative programs. This study identifies a structurally novel and selective MAPKAPK2 inhibitor with anti-cancer activity in pancreatic cancer cells. These findings support MAPKAPK2 as a potential therapeutic target and establish compound 77501 as a promising chemical starting point for MAPKAPK2-targeted drug discovery.