Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84 Lund, Sweden.
J Med Chem. 2021 Nov 11;64(21):15858-15867. doi: 10.1021/acs.jmedchem.1c01168. Epub 2021 Nov 3.
A novel natural small molecule, voacangine (Voa), has been discovered as a potent antiangiogenic compound. Notably, Voa directly binds the kinase domain of the vascular endothelial growth factor receptor 2 (VEGFR2) and thereby inhibits downstream signaling. Herein, we developed synthetic small molecules based on the unique chemical structure of Voa that directly and specifically target and modulate the kinase activity of VEGFR2. Among these Voa structure analogues, Voa analogue 19 (V19) exhibited increased antiangiogenic potency against VEGF-induced VEGFR2 phosphorylation without cytotoxic effects. Moreover, treatment with V19 resulted in significant tumor cell death in a mouse xenograft model. In conclusion, this new VEGFR2 modulator, inspired from the rigid scaffold of a natural compound, Voa, is presented as a potent candidate in the development of new antiangiogenic agents.
一种新型天然小分子，沃卡辛（Voa），已被发现是一种有效的抗血管生成化合物。值得注意的是，Voa 直接结合血管内皮生长因子受体 2（VEGFR2）的激酶结构域，从而抑制下游信号转导。在此，我们基于 Voa 的独特化学结构开发了合成小分子，这些小分子可直接、特异性地靶向和调节 VEGFR2 的激酶活性。在这些 Voa 结构类似物中，Voa 类似物 19（V19）在不具有细胞毒性的情况下，对 VEGF 诱导的 VEGFR2 磷酸化显示出增强的抗血管生成效力。此外，V19 治疗导致在小鼠异种移植模型中肿瘤细胞大量死亡。总之，这种源自天然化合物刚性支架的新型 VEGFR2 调节剂作为新型抗血管生成剂的候选药物具有很大潜力。
