title: Design, synthesis and SAR exploration of tri-substituted 1,2,4-triazoles as inhibitors of the annexin A2-S100A10 protein interaction.
abstract: Recent target validation studies have shown that inhibition of the protein interaction between annexin A2 and the S100A10 protein may have potential therapeutic benefits in cancer. Virtual screening identified certain 3,4,5-trisubstituted 4H-1,2,4-triazoles as moderately potent inhibitors of this interaction. A series of analogues were synthesized based on the 1,2,4-triazole scaffold and were evaluated for inhibition of the annexin A2-S100A10 protein interaction in competitive binding assays. 2-[(5-{[(4,6-Dimethylpyrimidin-2-yl)sulfanyl]methyl}-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-N-[4-(propan-2-yl)phenyl]acetamide (36) showed improved potency and was shown to disrupt the native complex between annexin A2 and S100A10.
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
authors.forename: Tummala R K
authors.initials: TR
authors.lastname: Reddy
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
authors.forename: Chan
authors.initials: C
authors.lastname: Li
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Guo
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom. Electronic address: lodewijk.dekker@nottingham.ac.uk.
authors.forename: Lodewijk V
authors.initials: LV
authors.lastname: Dekker
mesh_terms: D017306:Annexin A2 / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D017306:Annexin A2; D014230:Triazoles; C045575:1,2,4-triazole
keywords: Annexins; Docking; S100 proteins; Triazole