- Title
- Targeting the S100A2-p53 Interaction with a Series of 3,5-Bis(trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity
- Creator
- 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
- Relation
- ChemMedChem Vol. 16, Issue 18, p. 2851-2863
- Publisher Link
- http://dx.doi.org/10.1002/cmdc.202000949
- Publisher
- Wiley-Blackwell
- Resource Type
- journal article
- Date
- 2021
- Description
- 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.
- Subject
- pancreatic cancer; S100A2; p53; focuse libraries; protein-protein interaction; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1472107
- Identifier
- uon:48769
- Identifier
- ISSN:1860-7179
- Language
- eng
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