Domainex Ltd, NCE Discovery, 324 Cambridge Science Park, Cambridge CB4 0WG, UK.
J Med Chem. 2010 Mar 11;53(5):2215-26. doi: 10.1021/jm901755g.
We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.
我们报告了 EG00229，即第一个小分子 VEGF-A 受体神经纤毛蛋白 1（NRP1）配体的分子设计和合成，并通过 NMR 光谱和 X 射线晶体学对 NRP1-配体复合物进行了结构表征。突变研究将 VEGF-A 的结合定位在 NRP1 b1 结构域，并且 NMR 显示 VEGF-A 的肽片段也结合在相同的部位，为小分子设计提供了基础。化合物 2 显示抑制 VEGF-A 与 NRP1 的结合，并减弱内皮细胞中 VEGFR2 的磷酸化。还观察到对内皮细胞迁移的抑制。化合物 2 降低了 A549 肺癌细胞的活力，并且当与紫杉醇和 5-氟尿嘧啶联合使用时增加了它们的细胞毒性。这些研究为设计特异性小分子抑制剂以抑制配体与 NRP1 的结合提供了基础。
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