Rational design of apoptosis signal-regulating kinase 1 inhibitors: Discovering novel structural scaffold

• Published in: European journal of medicinal chemistry 2013-03, Vol.61, p.104-115
• Main Authors: Volynets, Galyna P., Bdzhola, Volodymyr G., Golub, Andriy G., Synyugin, Anatoliy R., Chekanov, Maksym A., Kukharenko, Oleksandr P., Yarmoluk, Sergiy M.
• Format: Article
• Language: English
• Subjects: Apoptosis signal-regulating kinase 1; ASK1; Butyrates - chemical synthesis; Butyrates - chemistry; Butyrates - pharmacology; Caproates - chemical synthesis; Caproates - chemistry; Caproates - pharmacology; Compound library; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Humans; Inhibitor; Kinase assay; MAP Kinase Kinase Kinase 5 - antagonists & inhibitors; MAP Kinase Kinase Kinase 5 - metabolism; Models, Molecular; Molecular Dynamics Simulation; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Structure-Activity Relationship; Thiazolidines - chemical synthesis; Thiazolidines - chemistry; Thiazolidines - pharmacology; Virtual screening
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.09.022

Increased activity of apoptosis signal-regulating kinase 1 (ASK1) is associated with a number of human disorders and the inhibitors of ASK1 may become important compounds for pharmaceutical application. Here we report novel ASK1 inhibitor scaffold, namely 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one, that has been identified using virtual screening and biochemical tests. A series of derivatives has been synthesized and evaluated in vitro towards human protein kinase ASK1. It was revealed that the most active compounds 4-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid and 6-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)hexanoic acid inhibit ASK1 with IC50 of 0.2 μM. Structure–activity relationships of 33 derivatives of 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one have been studied and binding mode of this chemical class has been predicted. [Display omitted] ► ASK1 inhibitor scaffold has been identified using virtual screening. ► A series of derivatives has been synthesized and tested in vitro. ► The most active compounds inhibit ASK1 with IC50 values in the range of 0.2–0.3 μM. ► Structure–activity relationships of 33 tested derivatives have been studied.