4.7 Article

Discovery of Small Molecules Simultaneously Targeting NAD(P)H:Quinone Oxidoreductase 1 and Nicotinamide Phosphoribosyltransferase: Treatment of Drug-Resistant Non-small-Cell Lung Cancer

期刊

JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 11, 页码 7746-7769

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00077

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资金

  1. National Natural Science Foundation of China [81773559, 82161138005, 22107117, 22001267]
  2. Double First-Class University Project [CPU2018GY03]
  3. China Postdoctoral Science Foundation [2021M693516]
  4. Postdoctoral Research Program of Jiangsu Province [2021K218B]

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Targeting NAD(+) metabolism is an effective anticancer strategy. Small molecules that simultaneously target NQO1 and NAMPT were discovered, and one of these compounds, 10d, showed excellent in vivo antitumor efficacy without significant toxicity.
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.

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