title: 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.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Sergiy A
authors.initials: SA
authors.lastname: Starosyla
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Galyna P
authors.initials: GP
authors.lastname: Volynets
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Sergiy S
authors.initials: SS
authors.lastname: Lukashov
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Oksana B
authors.initials: OB
authors.lastname: Gorbatiuk
authors.affiliation: OTAVA Ltd., 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K0C3, Canada.
authors.forename: Andriy G
authors.initials: AG
authors.lastname: Golub
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Volodymyr G
authors.initials: VG
authors.lastname: Bdzhola
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine. Electronic address: sergiy@yarmoluk.org.ua.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Yarmoluk
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D057075:Enzyme Assays; D057166:High-Throughput Screening Assays; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000737:chemistry; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry*; D011994:Recombinant Proteins; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry*; D014584:User-Computer Interface
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013844:Thiazoles; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human
keywords: Apoptosis signal-regulating kinase 1, ASK1; Compound library; Inhibitor; Kinase assay; Virtual screening