Pancreatic cancer (PC) is characterized as one of the deadliest malignancies and its treatment is a great challenge to clinical oncologists. Expression of COX-2 is detectable in 75% of PCs among which 50% showed overexpression, suggesting the importance of COX-2 enzyme and its metabolic product prostaglandin E2 (PGE2) in PC. Here the authors report the synthesis and biological activity of a novel COX-2 inhibitor, FPA-306, and its effects on PC cells with different levels of COX-2 expression. Using MTT assay, the authors found a significant growth inhibition of BxPC-3 cells treated by FPA-306 with an IC50 of 10 μmol/L, which was lower than that of ketoprofen (IC50 = 35.4 μmol/L) and celecoxib (IC50 > 100 μmol/L). There was no such effect found in MIAPaCa cell line, which does not express COX-2. The authors also found dose dependent reduction in cell survival and induction of apoptosis by FPA-306 treatment in BxPC-3 cells but not in MIAPaCa cells. These results were correlated with apoptosis data and secreted PGE2 levels. The molecular modeling of FPA-306 in the COX-2 active site showed that FPA-306 is potentially able to inhibit the activity of enzyme by blocking the active site, thereby resulting in decreased PGE2 production. The authors also found a significant reduction of COX-2 at the mRNA and protein levels together with downregulation of NF-κB DNA binding activity and its downstream genes, Bcl-2 and survivin. These results suggest that FPA-306 is an effective and potent agent in inhibiting the growth of PC cells. © 2006 Wiley-Liss, Inc.