2. Academic Validation
  3. 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

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.
Sergiy A Starosyla 1,  Galyna P Volynets 1,  Sergiy S Lukashov 1,  Oksana B Gorbatiuk 1,  Andriy G Golub 2,  Volodymyr G Bdzhola 1,  Sergiy M Yarmoluk 3
Affiliations

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: [email protected].
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.

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