1. Rational design of apoptosis signal-regulating kinase 1 inhibitors: Discovering novel structural scaffold
- Author
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Volynets, Galyna P., Bdzhola, Volodymyr G., Golub, Andriy G., Synyugin, Anatoliy R., Chekanov, Maksym A., Kukharenko, Oleksandr P., and Yarmoluk, Sergiy M.
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APOPTOSIS , *KINASE inhibitors , *SCAFFOLD proteins , *PROTEIN structure , *PHARMACEUTICAL chemistry , *PROTEIN kinases , *VASCULAR endothelial growth factors , *MONOCYTE chemotactic factor - Abstract
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. [Copyright &y& Elsevier]
- Published
- 2013
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