logo
English (United Kingdom)Ukrainian (UA)
RESEARCH Protein Kinase Inhibitors ASK1 Inhibitors Evaluation of 2-Thioxo-thiazolidin-4-ones Derivatives as Inhibitors of ASK1

Evaluation of 2-Thioxo-thiazolidin-4-ones Derivatives as Inhibitors of ASK1

In order to discover novel ASK1 inhibitors we have performed screening program, using both in silico and in vitro approaches. The system based on DOCK4.0 package was used to study receptor-ligand flexible docking. The virtual screening experiments were carried out targeting the ATP binding site of ASK1 by searching the commercially available compound library of diverse chemical classes provided by Otava, Ltd. The best-ranking compounds have been selected and taken for the kinase assay study.

In vitro experiments revealed that a number of 2-thioxo-thiazolidin-4-one derivatives showed inhibitory activity towards ASK1. The most active compound inhibited ASK1 in a dose-dependent manner with IC50=2 µM. Then, we performed in-depth study of this chemical class using the pre-selected library of 8,425 2-thioxo-thiazolidin-4-one derivatives. Ten compounds were selected and taken for the kinase assay. Compound 2-{5-[5-(3,4-dichloro-phenyl)-furan-2-ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propanoic acid (PFTA-1) possesses submicromolar activity (IC50 = 0.65 µM). Our preliminary selectivity studies have demonstrated that compound seems to be potent inhibitor of ASK1.

PFTA-1
Figure 1. The binding mode of PFTA-1 in the active site of the ASK1 catalytic subunit. Hydrogen bonds are shown by the dotted lines.

To inspect the binding mode of studied compounds we analyzed ASK1 complexes with 2-thioxo-thiazolidin-4-one derivatives generated by molecular docking software. It turned out that peculiarity of the PFTA-1 in the comparison to other nine compounds is its ability to bind simultaneously to the part of kinase domain known as "hinge region" and the phosphate-binding region of the ATP-binding cleft.

Our further goal was to use structural core of PFTA-1 to develop more potent and selective inhibitors of ASK1. 32 derivatives of 5-(5-phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one were synthesized and tested.

Figure 2. Structure-activity relationships of 5-(5-phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one derivatives.
Figure 2. Structure-activity relationships of 5-(5-phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one derivatives.

Comparing SAR and modeling data, it can be assumed that the substituents on the phenyl ring only slightly affect the potency of investigated compounds. It was also turned out that the carboxylic acid in the structure of 5-(5-phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one derivatives is necessary for inhibitory activity toward ASK1. The most active compound has R1 = butyric acid. The IC50 of this optimized inhibitor equals 0.2 µM.


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

Other kinase inhibitors research:

CK2 Inhibitors
3-carboxy-4(1H)-quinolones Image
This CK2 inhibitors were revealed and evaluated to be a CK2 inhibitors after...



 

ASK1 Inhibitors

 

FGFR1 Inhibitors
N-phenylthieno[2,3-d]pyrimidin-4-amines Image
Thienopyrimidine derivatives have attracted great interest as protein kinase...



 

© 2012 All rights reserved
footer logo