Targeting the S100A2-p53 interactions with a series of novel 3,5-bistrifluoromethylbenzene sulfonamides: Synthesis and cytotoxicity.

Sun, Jufeng; Ambrus, Joey I; Russell, Cecilia C; Baker, Jennifer R; Cossar, Peter J; Pirinen, Melanie J; Sakoff, Jennette A; Scarlett, Christopher J; McCluskey, Adam

In silico approaches identified 1 , N -(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 µM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused library synthesis (3 libraries, 24 compounds total) and cytotoxicity screening identified a propyl alkyl diamine spacer as optimal; the nature of the terminal phenyl substituent had limited impact on observed cytotoxicity, whereas N -methylation was detrimental to activity. In total 15 human cancer cell lines were examined, with most analogues showing broad spectrum activity. Near uniform activity was observed against a panel of six pancreatic cancer cell lines: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1. In all cases there was good to excellent correlation between the predicted docking pose in the S100A2-p53 binding groove and the observed cytotoxicity, especially in the pancreatic cancer cell line with high endogenous S100A2 expression. This supports S100A2 as a pancreatic cancer drug target.