Identification of 3H-naphtho[1,2,3-de]quinoline-2,7-diones as Inhibitors of ASK1

Virtual screening and biochemical screening allowed us to identify small-molecule inhibitor of human protein kinase ASK1 among 3H-naphtho[1,2,3-de]quinoline-2,7-diones. In vitro experiments revealed that ethyl 2,7-dioxo-2,7-dihydro-3H-naphtho[1,2,3-de]quinoline-1-carboxylate (NQDI-1) inhibited ASK1 with IC₅₀ = 3 µM. Our preliminary selectivity studies have demonstrated that this compound is a selective inhibitor of ASK1.

Figure 1. The binding mode of NQDI-1 in the active site of the ASK1 catalytic subunit. Hydrogen bonds are shown by the dotted lines.

Accordingly to the in silico modeling results, the mechanism of ASK1 inhibition involves the hydrogen bond formation between carbonyl of NQDI-1 and ASK1 hinge region. These results strongly suggest that the core structure of this class of compounds can be used for the development of more potent and selective inhibitors of ASK1.

• Identification of 3H-naphtho[1,2,3-de]quinoline-2,7-diones as inhibitors of apoptosis signal-regulating kinase 1 (ASK1). Volynets GP, Chekanov MO, Synyugin AR, Golub AG, Kukharenko OP, Bdzhola VG, Yarmoluk SM. J Med Chem. 2011, 54(8): 2680-2686.