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Targeting the S100A2‐p53 Interaction with a Series of 3,5‐ Bis (trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity
Author(s) -
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
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000949
Subject(s) - cytotoxicity , trifluoromethyl , benzene , chemistry , series (stratigraphy) , stereochemistry , benzene derivatives , combinatorial chemistry , organic chemistry , chemical synthesis , biochemistry , biology , in vitro , alkyl , paleontology
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.