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

Sergiy A Starosyla; Galyna P Volynets; Sergiy S Lukashov; Oksana B Gorbatiuk; Andriy G Golub; Volodymyr G Bdzhola; Sergiy M Yarmoluk

doi:10.1016/j.bmc.2015.03.056

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

Bioorg Med Chem. 2015 May 15;23(10):2489-97. doi: 10.1016/j.bmc.2015.03.056. Epub 2015 Mar 28.

Authors

Sergiy A Starosyla¹, Galyna P Volynets¹, Sergiy S Lukashov¹, Oksana B Gorbatiuk¹, Andriy G Golub², Volodymyr G Bdzhola¹, Sergiy M Yarmoluk³

Affiliations

¹ Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
² OTAVA Ltd., 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K0C3, Canada.
³ Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine. Electronic address: sergiy@yarmoluk.org.ua.

PMID: 25882527
DOI: 10.1016/j.bmc.2015.03.056

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.

Keywords: Apoptosis signal-regulating kinase 1, ASK1; Compound library; Inhibitor; Kinase assay; Virtual screening.

Publication types

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

MeSH terms

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

Substances

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