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ID: ALA5154937
Journal: J Med Chem
Title: Discovery of Small Molecules Simultaneously Targeting NAD(P)H:Quinone Oxidoreductase 1 and Nicotinamide Phosphoribosyltransferase: Treatment of Drug-Resistant Non-small-Cell Lung Cancer.
Authors: Zhang K, Wang K, Zhang X, Qian Z, Zhang W, Zheng X, Wang J, Jiang Y, Zhang W, Lu Z, Hao H, Jiang S.
Abstract: Targeting NAD+ metabolism has emerged as an effective anticancer strategy. Inspired by the synergistic antitumor effect between NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates increasing the NAD consumption and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors hampering the NAD synthesis, first-in-class small molecules simultaneously targeting NQO1 and NAMPT were identified through structure-based design. In particular, compound 10d is an excellent NQO1 substrate that is processed faster than TSA by NQO1 and exhibited a slightly decreased NAMPT inhibitory potency than that of FK866. It can selectively inhibit the proliferation of NQO1-overexpressing A549 cells and taxol-resistant A549/taxol cells and also induce cell apoptosis and inhibit cell migration in an NQO1- and NAMPT-dependent manner in A549/taxol cells. Significantly, compound 10d demonstrated excellent in vivo antitumor efficacy in the A549/taxol xenograft models with no significant toxicity. This proof-of-concept study affirms the feasibility of discovering small molecules that target NQO1 and NAMPT simultaneously, and it also provides a novel, effective, and selective anticancer strategy.
CiteXplore: 35640078