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Identification of Fumarate Hydratase Inhibitors with Nutrient-Dependent Cytotoxicity
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2015-01-05 , DOI: 10.1021/ja5101257 Toshifumi Takeuchi 1 , Paul T Schumacker , Sergey A Kozmin
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2015-01-05 , DOI: 10.1021/ja5101257 Toshifumi Takeuchi 1 , Paul T Schumacker , Sergey A Kozmin
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Development of cell-permeable small molecules that target enzymes involved in energy metabolism remains important yet challenging. We describe here the discovery of a new class of compounds with a nutrient-dependent cytotoxicity profile that arises from pharmacological inhibition of fumarate hydratase (also known as fumarase). This finding was enabled by a high-throughput screen of a diverse chemical library in a panel of human cancer cell lines cultured under different growth conditions, followed by subsequent structure–activity optimization and target identification. While the highest cytotoxicity was observed under low glucose concentrations, the antiproliferative activities and inhibition of oxygen consumption rates in cells were distinctly different from those displayed by typical inhibitors of mitochondrial oxidative phosphorylation. The use of a photoaffinity labeling strategy identified fumarate hydratase as the principal pharmacological target. Final biochemical studies confirmed dose-dependent, competitive inhibition of this enzyme in vitro, which was fully consistent with the initially observed growth inhibitory activity. Our work demonstrates how the phenotypic observations combined with a successful target identification strategy can yield a useful class of pharmacological inhibitors of an enzyme involved in the operation of tricarboxylic acid cycle.
中文翻译：
具有营养依赖性细胞毒性的富马酸水合酶抑制剂的鉴定
开发针对参与能量代谢的酶的细胞渗透性小分子仍然重要但具有挑战性。我们在此描述了一类新化合物的发现，该化合物具有营养依赖性细胞毒性特征，该化合物源自富马酸水合酶（也称为延胡索酸酶）的药理学抑制。这一发现是通过对在不同生长条件下培养的一组人类癌细胞系中的多样化化学库进行高通量筛选，然后进行随后的结构-活性优化和靶标鉴定而实现的。虽然在低葡萄糖浓度下观察到最高的细胞毒性，但细胞中的抗增殖活性和耗氧率抑制与典型的线粒体氧化磷酸化抑制剂所表现出的明显不同。使用光亲和标记策略将富马酸水合酶确定为主要药理学靶点。最终的生化研究证实了这种酶在体外的剂量依赖性、竞争性抑制，这与最初观察到的生长抑制活性完全一致。我们的工作证明了表型观察与成功的靶标识别策略相结合如何能够产生一类与三羧酸循环操作有关的酶的有用药理学抑制剂。
更新日期：2015-01-05
中文翻译：
具有营养依赖性细胞毒性的富马酸水合酶抑制剂的鉴定
开发针对参与能量代谢的酶的细胞渗透性小分子仍然重要但具有挑战性。我们在此描述了一类新化合物的发现，该化合物具有营养依赖性细胞毒性特征，该化合物源自富马酸水合酶（也称为延胡索酸酶）的药理学抑制。这一发现是通过对在不同生长条件下培养的一组人类癌细胞系中的多样化化学库进行高通量筛选，然后进行随后的结构-活性优化和靶标鉴定而实现的。虽然在低葡萄糖浓度下观察到最高的细胞毒性，但细胞中的抗增殖活性和耗氧率抑制与典型的线粒体氧化磷酸化抑制剂所表现出的明显不同。使用光亲和标记策略将富马酸水合酶确定为主要药理学靶点。最终的生化研究证实了这种酶在体外的剂量依赖性、竞争性抑制，这与最初观察到的生长抑制活性完全一致。我们的工作证明了表型观察与成功的靶标识别策略相结合如何能够产生一类与三羧酸循环操作有关的酶的有用药理学抑制剂。
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