Vander Heiden Matthew G, Christofk Heather R, Schuman Eli, Subtelny Alexander O, Sharfi Hadar, Harlow Edward E, Xian Jun, Cantley Lewis C
Dana-Farber Cancer Institute, Boston, MA 02115, United States.
Biochem Pharmacol. 2010 Apr 15;79(8):1118-24. doi: 10.1016/j.bcp.2009.12.003. Epub 2009 Dec 11.
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 1,00,000 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.
源自不同组织类型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。癌细胞与正常细胞之间的这种代谢差异可被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，并且先前的研究表明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的是PKM2以外的丙酮酸激酶亚型，对PKM2进行选择性靶向为针对细胞代谢进行癌症治疗提供了一个机会。PKM2与相关的M1剪接变体（PKM1）具有相同的催化位点。然而，由于PKM2含有一个用于变构调节的独特区域，所以有可能实现亚型选择性抑制。我们筛选了一个包含超过100,000个小分子的文库以鉴定此类抑制剂。鉴定出的针对PKM2的抑制剂主要分为三个不同的结构类别。最有效的PKM2抑制剂在生长因子信号缺失后导致糖酵解减少和细胞死亡增加。这种效应至少部分是由于对靶点PKM2的抑制，因为在经过基因工程改造以表达PKM1的细胞中观察到的细胞死亡较少。这些数据表明用小分子对PKM2进行亚型选择性抑制是可行的，并支持这样一种假说，即抑制癌细胞中的葡萄糖代谢是治疗人类恶性肿瘤的一种可行策略。
