Targeting the S100A2-p53 Interaction with a Series of 3,5-Bis(trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity
- ChemMedChem. 2021 Sep 16;16(18):2851-2863. doi: 10.1002/cmdc.202000949.
- 1. Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia.
- 2. Medicinal Chemistry, School of Pharmacy, Binzhou Medical University, Yantai, 264003, China.
- 3. School of Environmental & Life Sciences, The University of Newcastle, Ourimbah, NSW, 2258, Australia.
- 4. Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Newcastle Hospital, Edith Street, Waratah, NSW, 2298, Australia.
In silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of the 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 (three 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.