JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 7.3
Yixian Fu,Yahui Huang,Chenchen Zhou,Xinge Li,Guoqiang Dong,Min Huang,Jian Ding,Chunquan Sheng
Nicotinamide adenine dinucleotide (NAD) is essentially involved in many biological processes of cancer cells, yet chemical intervention of NAD biosynthesis failed to obtain an optimal therapeutic benefit. We herein developed a new strategy to induce catastrophic NAD depletion by concurrently impairing NAD synthesis and promoting NAD consumption. We designed a series of new compounds that conjugate an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD salvage pathway, with a DNA-alkylating agent. Among them, compound 11b exhibited potent anticancer efficacy in cancer cell lines and mouse tumor models with intrinsic resistance to the parent compound FK866 or chlorambucil. Compound 11b caused catastrophic NAD depletion via a synergistic effect between the NAD salvage pathway blockade and DNA damage-triggered NAD consumption. Our findings suggest a new intervention strategy for causing catastrophic NAD depletion in cancer cells and provide basis for the development of new inhibitors targeting NAD metabolism.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
SCIENCE
·
2025
·
IF 45.8
Zhifeng Zeng,Zeyu Hu,Ruiliang Zhao,Jikai Rao,Mario Rodríguez Mestre,Yanqiu Liu,Shunhang Liu,Hao Feng,Yu Chen,Huan He,Nuo Chen,Jinshui Zheng,Donghai Peng,Min Luo,Qunxin She,Rafael Pinilla-Redondo,Wenyuan Han
Signaling from pathogen sensing to effector activation is a fundamental principle of cellular immunity. While cyclic (oligo)nucleotides have emerged as key signaling molecules, the existence of other messengers remains largely unexplored. Here, we reveal a bacterial anti-phage system that mediates immune signaling through nucleobase modification. Immunity is triggered by phage nucleotide kinases, which, combined with the system-encoded adenosine deaminase, produce deoxyinosine 5′-triphosphate (dITP) as immune messengers. The dITP signal activates downstream effector to mediate cellular NAD+ depletion, resulting in population-level defense through the death of infected cells. To counteract immune signaling, phages deploy specialized enzymes that deplete cellular dAMP, the precursor of dITP messengers. Our findings uncover a nucleobase modification-based anti-phage signaling pathway, establishing noncanonical nucleotides as a new type of immune messengers in bacteria.
研究领域:
微生物学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cancers
·
2025
·Vol. 18
·期 1
·92
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IF 4.4
Hao Dong,Yuan Gao,Dongyue Jiang,Chenjie Feng,Xinyue Gu,Xiyunyi Cai,Yulin Liu,Guangyu Zhang,Jiacheng Wen,Weiwei Diao,Ying Zhou,Ruixin Li,Dayang Xu,Weijia Xie,Liang Wu
Simple SummaryHepatocellular carcinoma (HCC) is characterized by high incidence and mortality rates, yet effective therapeutic drugs remain scarce, creating an urgent need for viable treatment strategies. This study aimed to develop novel small-molecule anti-HCC agents based on the naturally derived antitumor compound caffeic acid phenethyl ester (CAPE), evaluate their efficacy against HCC, and investigate their underlying pharmacological mechanisms. A total of 28 structurally analogous small-molecule derivatives were synthesized, from which the most potent compound, designated WX006, was selected. Using an integrated approach encompassing molecular biology, cell biology, computational biology, and multi-omics analysis, we demonstrated that WX006 effectively depletes Nicotinamide adenine dinucleotide (NAD+) in HCC cells by binding to NADH: Ubiquinone Oxidoreductase Core Subunit S2 (NDUFS2), thereby disrupting mitochondrial function and intracellular metal ion homeostasis. This study provides valuable and independent insights into the development of derivatives based on the natural small molecule CAPE and establishes a further foundation for the advancement of anti-HCC therapies.Background: In this study, 28 caffeic acid phenethyl ester (CAPE) derivatives were designed and synthesized, and their anti-proliferative activities were evaluated against two representative human hepatocellular carcinoma (HCC) cell lines. The half-maximal inhibitory concentration (IC50) was used as the activity metric. Among these derivatives, compound WX006 displayed the most potent anti-proliferative effect, with IC50values of 3.332 μM and 3.764 μM after 48 h of treatment, significantly lower than those of the parent compound CAPE. Consequently, WX006 was selected for further investigation into its antitumor efficacy and underlying mechanisms. Methods: To investigate the pharmacological mechanism of WX006, we employed a combination of high-throughput transcriptomics, metabolomics, and mitochondrial function analysis to elucidate its intracellular mechanisms of action. Results: WX006 disrupts cytoplasmic-mitochondrial metal ion homeostasis, triggering ferroptosis and cuproptosis through iron-copper dysregulation. Computational modeling revealed that WX006 selectively inhibits mitochondrial NDUFS2 subunit of respiratory chain complex I, which may induce NAD+exhaustion and consequent energy metabolism collapse in tumor cells. These “metabolism & metal homeostasis” dual mechanisms collectively underpin its robust anti-tumor effects. Therapeutic efficacy of WX006 was further validated in murine H22 ectopic xenograft and Hepa1-6-Luc orthotopic xenograft models, where WX006 exhibited superior tumor suppression compared to sorafenib, alongside favorable safety profiles. Conclusions: Our findings establish a foundational rationale for further pharmaceutical development of CAPE derivates as a promising therapeutic candidate for hepatocellular carcinoma.
研究领域:
肿瘤学
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药物化学
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分子生物学
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癌症药理学
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代谢组学
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计算生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）