Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice
Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice
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DOI：
10.1038/80257
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发表时间：
2000-10-01
影响因子：
46.9
通讯作者：
Sebti, SM
中科院分区：
文献类型：
--
作者：
Blaskovich, MA;Lin, Q;Sebti, SM
我们设计了一种分子GFB-111，它与血小板衍生生长因子（PDGF）结合，阻止其与受体酪氨酸激酶结合，并阻断PDGF诱导的受体自磷酸化，Erk 1和Erk 2激酶的激活以及DNA合成。GFB-111对PDGF的选择性高于EGF、IGF-1、aFGF、bFGF和HRG β（IC 50值> 100 μ M），但抑制VEGF诱导的Flk-1酪氨酸磷酸化和Erk 1/Erk 2活化，IC 50为10 μ M。GFB-111治疗荷人肿瘤的裸鼠导致肿瘤生长和血管生成的显著抑制。结果表明，设计新的生长因子结合分子具有有效的抗癌和抗血管生成活性的可行性。
We have designed a molecule, GFB-111, that binds to platelet-derived growth factor (PDGF), prevents it from binding to its receptor tyrosine kinase, and blocks PDGF-induced receptor autophosphorylation, activation of Erk1 and Erk2 kinases, and DNA synthesis. GFB-111 is highly potent (IC50 = 250 nM) and selective for PDGF over EGF, IGF-1, aFGF, bFGF, and HRG beta (IC50 values > 100 mu M), but inhibits VEGF-induced Flk-1 tyrosine phosphorylation and Erk1/Erk2 activation with an IC50 of 10 mu M. GFB-111 treatment of nude mice bearing human tumors resulted in significant inhibition of tumor growth and angiogenesis. The results demonstrate the feasibility of designing novel growth factor-binding molecules with potent anticancer and antiangiogenic activity.