Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin
Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin
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DOI：
10.1016/s1074-5521(97)90198-8
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发表时间：
1997-06-01
影响因子：
--
通讯作者：
Liu, JO
中科院分区：
文献类型：
--
作者：
Griffith, EC;Su, Z;Liu, JO
背景：血管生成，即新血管的形成，是肿瘤生长所必需的。因此，抑制血管生成是一种很有前景的癌症治疗方法。两种天然产物，富马青霉素和卵黄霉素，被发现是血管生成的有效抑制剂，因为它们抑制内皮细胞的增殖。富马青霉素的类似物AGM-1470目前正在进行临床试验，用于治疗多种癌症。这些天然药物抑制血管生成的潜在分子机制尚不清楚。结果：AGM-1470和ovalicin都与一个共同的双功能蛋白结合，通过质谱鉴定为2型蛋氨酸氨基肽酶（MetAP2）。该蛋白还作为真核起始因子2 α (eIF-2 α)磷酸化的抑制剂。这两种药物都能有效抑制MetAP2的蛋氨酸氨基肽酶活性，而不影响其阻断eIF-2 α磷酸化的能力。在真核生物中发现了两种类型的蛋氨酸氨基肽酶，但只有2型酶被药物抑制。合成了一系列富马青霉素和卵黄霉素类似物，并测定了它们抑制内皮细胞增殖和蛋氨酸氨基肽酶活性的能力。在这两种活动之间发现了显著的相关性。结论：MetAP2蛋白是AGM-1470和卵黄蛋白的共同分子靶点。这一发现提示MetAP2可能在内皮细胞的增殖中发挥关键作用，并可能成为开发新的抗血管生成药物的有希望的靶点。
Background: Angiogenesis, the formation of new blood vessels, is essential for tumor growth. The inhibition of angiogenesis is therefore emerging as a promising therapy for cancer. Two natural products, fumagillin and ovalicin, were discovered to be potent inhibitors of angiogenesis due to their inhibition of endothelial cell proliferation. An analog of fumagillin, AGM-1470, is currently undergoing clinical trials for the treatment of a variety of cancers. The underlying molecular mechanism of the inhibition of angiogenesis by these natural drugs has remained unknown.Results: Both AGM-1470 and ovalicin bind to a common bifunctional protein, identified by mass spectrometry as the type 2 methionine aminopeptidase (MetAP2). This protein also acts as an inhibitor of eukaryotic initiation factor 2 alpha (eIF-2 alpha) phosphorylation. Both drugs potently inhibit the methionine aminopeptidase activity of MetAP2 without affecting its ability to block eIF-2 alpha phosphorylation. There are two types of methionine aminopeptidase found in eukaryotes, but only the type 2 enzyme is inhibited by the drugs. A series of analogs of fumagillin and ovalicin were synthesized and their potency for inhibition of endothelial cell proliferation and inhibition of methionine aminopeptidase activity was determined. A significant correlation was found between the two activities.Conclusions: The protein MetAP2 is a common molecular target for both AGM-1470 and ovalicin. This finding suggests that MetAP2 may play a critical role in the proliferation of endothelial cells and may serve as a promising target for the development of new anti-angiogenic drugs.