Rational Design of Apoptosis Signal-Regulating Kinase 1 Inhibitors: Discovering Novel Structural Scaffold

Our manuscript on new ASK1 inhibitors has been published in European Journal of Medicinal Chemistry

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 30 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.

• Rational design of apoptosis signal-regulating kinase 1 inhibitors: discovering novel structural scaffold. Volynets GP, Bdzhola VG, Golub AG, Synyugin AR, Chekanov MA, Kukharenko OP, Yarmoluk SM. Eur J Med Chem. 2013, 61:104-115.