Identification of apoptosis signal-regulating kinase 1 (ASK1) inhibitors among the derivatives of benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one.

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) plays important roles in the pathogenesis of type 1 and type 2 diabetes, autoimmune disorders, cancer and neurodegenerative diseases suggesting that small compounds inhibiting ASK1 could be used for the treatment of these pathologies. We have identified novel chemical class of ASK1 inhibitors, namely benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one, using molecular modeling techniques. It was found that the most active compound 1-(6-fluoro-benzothiazol-2-yl)-3-hydroxy-5-[3-(3-methyl-butoxy)-phenyl]-4-(2-methyl-2,3-dihydro-benzofuran-5-carbonyl)-1,5-dihydro-pyrrol-2-one (BPyO-34) inhibits ASK1 with IC50 of 0.52μM in vitro in kinase assay. The structure-activity relationships of 34 derivatives of benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one have been studied and binding mode of this chemical class has been proposed.

• Authors: Sergiy A Starosyla, Galyna P Volynets, Sergiy S Lukashov, Oksana B Gorbatiuk, Andriy G Golub, Volodymyr G Bdzhola, Sergiy M Yarmoluk
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 10 Pg. 2489-97 (May 15 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 25882527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Hypoglycemic Agents
• Immunologic Factors
• Neuroprotective Agents
• Protein Kinase Inhibitors
• Pyrroles
• Recombinant Proteins
• Small Molecule Libraries
• Thiazoles
• MAP Kinase Kinase Kinase 5
• MAP3K5 protein, human

Topics

• Antineoplastic Agents (chemical synthesis, chemistry)
• Binding Sites
• Enzyme Assays
• High-Throughput Screening Assays
• Humans
• Hypoglycemic Agents (chemical synthesis, chemistry)
• Immunologic Factors (chemical synthesis, chemistry)
• MAP Kinase Kinase Kinase 5 (antagonists & inhibitors, chemistry)
• Neuroprotective Agents (chemical synthesis, chemistry)
• Protein Binding
• Protein Kinase Inhibitors (chemical synthesis, chemistry)
• Pyrroles (chemical synthesis, chemistry)
• Recombinant Proteins
• Small Molecule Libraries (chemical synthesis, chemistry)
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, chemistry)
• User-Computer Interface