Target Discovery of Selective Non-Small-Cell Lung Cancer Toxins Reveals Inhibitors of Mitochondrial Complex I,ACS Chemical Biology

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Target Discovery of Selective Non-Small-Cell Lung Cancer Toxins Reveals Inhibitors of Mitochondrial Complex I
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-24 , DOI: 10.1021/acschembio.9b00734
Nikhil Madhusudhan _{1,

2,

3} , Bin Hu ₁ , Prashant Mishra ₄ , Josè F Calva-Moreno ₂ , Khushbu Patel ₅ , Richard Boriack ₆ , Joseph M Ready ₁ , Deepak Nijhawan _{1,

3,

7}

Affiliation

Selective toxicity among cancer cells of the same lineage is a hallmark of targeted therapies. As such, identifying compounds that impair proliferation of a subset of non-small-cell lung cancer (NSCLC) cell lines represents one strategy to discover new drugs for lung cancer. Previously, phenotypic screens of 202 103 compounds led to the identification of 208 selective NSCLC toxins (McMillan, E. A., Cell, 2018, 173, 864). The mechanism of action for the majority of these compounds remains unknown. Here, we discovered the target for a series of quinazoline diones (QDC) that demonstrate selective toxicity among 96 NSCLC lines. Using photoreactive probes, we found that the QDC binds to both mitochondrial complex I of the electron transport chain and hydroxyacyl CoA dehydrogenase subunit alpha (HADHA), which catalyzes long-chain fatty acid oxidation. Inhibition of complex I is the on-target activity for QDC, while binding to HADHA is off-target. The sensitivity profile of the QDC across NSCLC lines correlated with the sensitivity profiles of six additional structurally distinct compounds. The antiproliferative activity of these compounds is also the consequence of binding to mitochondrial complex I, reflecting significant structural diversity among complex I inhibitors. Small molecules targeting complex I are currently in clinical development for the treatment of cancer. Our results highlight complex I as a target in NSCLC and report structurally diverse scaffolds that inhibit complex I.

中文翻译：

选择性非小细胞肺癌毒素的靶向发现揭示了线粒体复合物 I 的抑制剂

同一谱系癌细胞之间的选择性毒性是靶向治疗的标志。因此，鉴定损害非小细胞肺癌 (NSCLC) 细胞系子集增殖的化合物代表了一种发现肺癌新药的策略。此前，对 202 103 种化合物的表型筛选导致鉴定出 208 种选择性 NSCLC 毒素（麦克米兰，EA,细胞, 2018 , 173, 864). 大多数这些化合物的作用机制仍然未知。在这里，我们发现了一系列喹唑啉二酮 (QDC) 的靶点，这些靶点在 96 个 NSCLC 细胞系中表现出选择性毒性。使用光反应探针，我们发现 QDC 与电子传递链的线粒体复合物 I 和羟酰基辅酶 A 脱氢酶亚基 α (HADHA) 结合，后者催化长链脂肪酸氧化。复合物 I 的抑制是 QDC 的靶向活性，而与 HADHA 的结合是脱靶的。QDC 跨 NSCLC 线的敏感性特征与另外六种结构不同的化合物的敏感性特征相关。这些化合物的抗增殖活性也是与线粒体复合物 I 结合的结果，反映了复杂 I 抑制剂之间的显着结构多样性。针对复合物 I 的小分子目前正处于癌症治疗的临床开发阶段。我们的结果突出了复合物 I 作为 NSCLC 的靶标，并报告了抑制复合物 I 的结构多样的支架。

更新日期：2019-12-25

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