title: Rational design of apoptosis signal-regulating kinase 1 inhibitors: discovering novel structural scaffold.
abstract: 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.
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo Str., 03143 Kyiv, Ukraine.
authors.forename: Galyna P
authors.initials: GP
authors.lastname: Volynets
authors.forename: Volodymyr G
authors.initials: VG
authors.lastname: Bdzhola
authors.forename: Andriy G
authors.initials: AG
authors.lastname: Golub
authors.forename: Anatoliy R
authors.initials: AR
authors.lastname: Synyugin
authors.forename: Maksym A
authors.initials: MA
authors.lastname: Chekanov
authors.forename: Oleksandr P
authors.initials: OP
authors.lastname: Kukharenko
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Yarmoluk
mesh_terms: D002087:Butyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002208:Caproates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000591014:4-(5-((5-(4-bromophenyl)-2-furyl)methylene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid; C000591015:6-(5-((5-(4-bromophenyl)-2-furyl)methylene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)hexanoic acid; D002087:Butyrates; D002208:Caproates; D047428:Protein Kinase Inhibitors; D053778:Thiazolidines; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human