Identification of small molecule inhibitors of pyruvate kinase M2.
Identification of small molecule inhibitors of pyruvate kinase M2.
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DOI：
10.1016/j.bcp.2009.12.003
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发表时间：
2010-04-15
影响因子：
5.8
通讯作者：
Cantley, Lewis C.
中科院分区：
文献类型：
--
作者：
Vander Heiden, Matthew G.;Christofk, Heather R.;Schuman, Eli;Subtelny, Alexander O.;Sharfi, Hadar;Harlow, Edward E.;Xian, Jun;Cantley, Lewis C.
关键词：
不同组织类型产生的肿瘤的一个共同特征是依赖有氧糖酵解进行葡萄糖代谢。癌细胞和正常细胞之间的这种代谢差异可用于为患者带来治疗益处。癌细胞普遍表达糖酵解酶丙酮酸激酶（PKM2）的M2亚型，之前的工作已经证明PKM2的表达对于体内有氧糖酵解和细胞增殖是必需的。由于大多数正常组织表达除 PKM2 之外的丙酮酸激酶亚型，因此选择性靶向 PKM2 为癌症治疗提供了靶向细胞代谢的机会。 PKM2 具有与相关 M1 剪接变体 (PKM1) 相同的催化位点。然而，同工型选择性抑制是可能的，因为 PKM2 包含一个独特的变构调节区域。我们筛选了超过 100,000 个小分子的库来鉴定此类抑制剂。鉴定出的 PKM2 抑制剂主要分为三个不同的结构类别。最有效的 PKM2 抑制剂会导致糖酵解减少，并在生长因子信号传导丧失后增加细胞死亡。这种效应至少部分归因于 PKM2 的靶向抑制，因为在表达 PKM1 的细胞中观察到较少的细胞死亡。这些数据表明，用小分子选择性抑制 PKM2 异构体是可行的，并支持抑制癌细胞中葡萄糖代谢是治疗人类恶性肿瘤的可行策略的假设。
A common feature of tumors arising from diverse tissue types is a reliance on aerobic glycolysis for glucose metabolism. This metabolic difference between cancer cells and normal cells could be exploited for therapeutic benefit in patients. Cancer cells universally express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), and previous work has demonstrated that PKM2 expression is necessary for aerobic glycolysis and cell proliferation in vivo. Because most normal tissues express an isoform of pyruvate kinase other than PKM2, selective targeting of PKM2 provides an opportunity to target cell metabolism for cancer therapy. PKM2 has an identical catalytic site as the related M1 splice variant (PKM1). However, isoform selective inhibition is possible as PKM2 contains a unique region for allosteric regulation. We have screened a library of greater than 100,000 small molecules to identify such inhibitors. The inhibitors identified for PKM2 fell primarily into three distinct structural classes. The most potent PKM2 inhibitor resulted in decreased glycolysis and increased cell death following loss of growth factor signaling. At least part of this effect was due to on-target PKM2 inhibition as less cell death was observed in cells engineered to express PKM1. These data suggest that isoform selective inhibition of PKM2 with small molecules is feasible and support the hypothesis that inhibition of glucose metabolism in cancer cells is a viable strategy to treat human malignancy.
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影响因子：
9.3
作者：
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通讯作者：
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DOI：
10.1016/s0360-3016(01)01534-6
发表时间：
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影响因子：
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作者：
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通讯作者：
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