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

Galyna P Volynets; Volodymyr G Bdzhola; Andriy G Golub; Anatoliy R Synyugin; Maksym A Chekanov; Oleksandr P Kukharenko; Sergiy M Yarmoluk

doi:10.1016/j.ejmech.2012.09.022

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

Eur J Med Chem. 2013 Mar:61:104-15. doi: 10.1016/j.ejmech.2012.09.022. Epub 2012 Sep 21.

Authors

Galyna P Volynets¹, Volodymyr G Bdzhola, Andriy G Golub, Anatoliy R Synyugin, Maksym A Chekanov, Oleksandr P Kukharenko, Sergiy M Yarmoluk

Affiliation

¹ Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo Str., 03143 Kyiv, Ukraine.

PMID: 23041041
DOI: 10.1016/j.ejmech.2012.09.022

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Butyrates / chemical synthesis
Butyrates / chemistry
Butyrates / pharmacology*
Caproates / chemical synthesis
Caproates / chemistry
Caproates / pharmacology*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery*
Humans
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*

Substances

4-(5-((5-(4-bromophenyl)-2-furyl)methylene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid
6-(5-((5-(4-bromophenyl)-2-furyl)methylene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)hexanoic acid
Butyrates
Caproates
Protein Kinase Inhibitors
Thiazolidines
MAP Kinase Kinase Kinase 5
MAP3K5 protein, human