Griffith E C, Su Z, Turk B E, Chen S, Chang Y H, Wu Z, Biemann K, Liu J O
Center for Cancer Research, Massachusetts Institute of Technology, Department of Biology, Cambridge, MA 02139, USA.
Chem Biol. 1997 Jun;4(6):461-71. doi: 10.1016/s1074-5521(97)90198-8.
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.
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 2alpha (elF-2alpha) phosphorylation. Both drugs potently inhibit the methionine aminopeptidase activity of MetAP2 without affecting its ability to block elF-2alpha 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.
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.
血管生成，即新血管的形成，对肿瘤生长至关重要。因此，抑制血管生成正成为一种有前景的癌症治疗方法。两种天然产物，烟曲霉素和卵曲霉素，由于其对内皮细胞增殖的抑制作用而被发现是血管生成的有效抑制剂。烟曲霉素的一种类似物AGM - 1470目前正在进行多种癌症治疗的临床试验。这些天然药物抑制血管生成的潜在分子机制尚不清楚。
AGM - 1470和卵曲霉素都与一种共同的双功能蛋白结合，通过质谱鉴定为2型甲硫氨酸氨肽酶（MetAP2）。这种蛋白还作为真核起始因子2α（elF - 2α）磷酸化的抑制剂。两种药物都能有效抑制MetAP2的甲硫氨酸氨肽酶活性，而不影响其阻断elF - 2α磷酸化的能力。在真核生物中发现有两种类型的甲硫氨酸氨肽酶，但只有2型酶被这些药物抑制。合成了一系列烟曲霉素和卵曲霉素的类似物，并测定了它们抑制内皮细胞增殖和抑制甲硫氨酸氨肽酶活性的效力。发现这两种活性之间存在显著相关性。
蛋白MetAP2是AGM - 1470和卵曲霉素的共同分子靶点。这一发现表明，MetAP2可能在内皮细胞增殖中起关键作用，并且可能成为开发新型抗血管生成药物的有前景的靶点。
