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

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Discovery of Small Molecules Simultaneously Targeting NAD(P)H:Quinone Oxidoreductase 1 and Nicotinamide Phosphoribosyltransferase: Treatment of Drug-Resistant Non-small-Cell Lung Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-31 , DOI: 10.1021/acs.jmedchem.2c00077
Kuojun Zhang ₁ , Kaizhen Wang ₁ , Xiangyu Zhang ₁ , Zhenlong Qian ₁ , Wenbo Zhang ₁ , Xiao Zheng ₁ , Jiaying Wang ₁ , Yin Jiang ₁ , Wanheng Zhang ₁ , Zhiyu Lu ₁ , Haiping Hao ₁ , Sheng Jiang ₁

Affiliation

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.

中文翻译：

发现同时靶向 NAD(P)H：醌氧化还原酶 1 和烟酰胺磷酸核糖基转移酶的小分子：治疗耐药性非小细胞肺癌

靶向 NAD ⁺代谢已成为一种有效的抗癌策略。受 NAD(P)H:醌氧化还原酶 1 (NQO1) 底物增加 NAD 消耗和烟酰胺磷酸核糖基转移酶 (NAMPT) 抑制剂阻碍 NAD 合成的协同抗肿瘤作用的启发，鉴定了同时靶向 NQO1 和 NAMPT 的一流小分子通过基于结构的设计。特别是化合物10d是一种出色的 NQO1 底物，其对 NQO1 的处理速度比 TSA 更快，并且表现出比 FK866 略微降低的 NAMPT 抑制效力。它可以选择性地抑制过表达 NQO1 的 A549 细胞和抗紫杉醇的 A549/紫杉醇细胞的增殖，并在 A549/紫杉醇细胞中以 NQO1 和 NAMPT 依赖性方式诱导细胞凋亡和抑制细胞迁移。值得注意的是，化合物10d在 A549/紫杉醇异种移植模型中表现出优异的体内抗肿瘤功效，且无明显毒性。这项概念验证研究证实了发现同时靶向 NQO1 和 NAMPT 的小分子的可行性，并提供了一种新颖、有效和选择性的抗癌策略。

更新日期：2022-05-31

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