title: Identification of 3H-naphtho[1,2,3-de]quinoline-2,7-diones as inhibitors of apoptosis signal-regulating kinase 1 (ASK1).
abstract: Apoptosis signal-regulating kinase 1 (ASK1) has recently emerged as an attractive therapeutic target for the treatment of cardiac and neurodegenerative disorders. The selective inhibitors of ASK1 may become important compounds for the development of clinical agents. We have identified the ASK1 inhibitor among 3H-naphtho[1,2,3-de]quinoline-2,7-diones using receptor-based virtual screening. In vitro kinase assay revealed that ethyl 2,7-dioxo-2,7-dihydro-3H-naphtho[1,2,3-de]quinoline-1-carboxylate (NQDI-1) inhibited ASK1 with a K(i) of 500 nM. The competitive character of inhibition is demonstrated in Lineweaver-Burk plots. In our preliminary selectivity study this compound exhibited strong specific inhibitory activity toward ASK1.
authors: Institute of Molecular Biology and Genetics, NAS of Ukraine, Kyiv, Ukraine.
authors: Galyna P
authors: GP
authors: Volynets
authors: Maksym O
authors: MO
authors: Chekanov
authors: Anatoliy R
authors: AR
authors: Synyugin
authors: Andriy G
authors: AG
authors: Golub
authors: Oleksandr P
authors: OP
authors: Kukharenko
authors: Volodymyr G
authors: VG
authors: Bdzhola
authors: Sergiy M
authors: SM
authors: Yarmoluk
mesh_terms: D000818:Animals; D001060:Aporphines / Q000737:chemistry / Q000494:pharmacology*; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000592751:2,7-dioxo-2,7-dihydro-3H-naphtho(1,2,3-de)quinoline-1-carboxylate; D001060:Aporphines; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D015363:Quinolones; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse