1. Targeting the S100A2‐p53 Interaction with a Series of 3,5‐ Bis (trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity
- Author
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Jennifer R. Baker, Jennette A. Sakoff, Cecilia C. Russell, Peter J. Cossar, Jufeng Sun, Christopher J. Scarlett, Adam McCluskey, Joey I. Ambrus, and Melanie J. Pirinen
- Subjects
Cell Survival ,Stereochemistry ,In silico ,Triazole ,Antineoplastic Agents ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pancreatic cancer ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity ,Cell Proliferation ,Pharmacology ,Trifluoromethyl ,Chemotactic Factors ,Dose-Response Relationship, Drug ,Molecular Structure ,S100 Proteins ,Organic Chemistry ,Cancer ,medicine.disease ,Molecular Docking Simulation ,chemistry ,Docking (molecular) ,Cell culture ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Tumor Suppressor Protein p53 - Abstract
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.
- Published
- 2021