Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
Eur J Med Chem. 2019 Feb 15;164:440-447. doi: 10.1016/j.ejmech.2018.12.067. Epub 2018 Dec 28.
Aberrant angiogenesis is a hallmark of various diseases including cancers. VEGFR-2 inhibitors have been utilized as anti-angiogenic agents for several years. However, compensatory activation of various receptor tyrosine kinases (RTK) could induce the occurrence of resistance. We previously reported a series of multi-target inhibitors of VEGFR-2, Tie-2, and EphB4 as anti-angiogenic agents. These inhibitors might be a promising strategy to overcome the resistance induced by compensatory activation. In order to expand the structural diversity of these multiple RTK inhibitors, we described herein the design, synthesis, and evaluation of a novel class of triplet VEGFR-2/TIE-2/EphB4 inhibitors. The biological evaluation indicated that five compounds (6b, 6d, 6e, 7e, and 7g) exhibited simultaneous VEGFR-2/Tie-2/EphB4 inhibitory activities with IC values less than 50 nM.
异常血管生成是包括癌症在内的各种疾病的标志。VEGFR-2 抑制剂已被用作抗血管生成药物多年。然而，各种受体酪氨酸激酶（RTK）的代偿性激活可能会导致耐药性的发生。我们之前报道了一系列作为抗血管生成剂的多靶点 VEGFR-2、Tie-2 和 EphB4 抑制剂。这些抑制剂可能是克服由代偿性激活引起的耐药性的一种有前途的策略。为了扩展这些多 RTK 抑制剂的结构多样性，我们在此描述了一类新型三联 VEGFR-2/TIE-2/EphB4 抑制剂的设计、合成和评价。生物学评价表明，有 5 种化合物（6b、6d、6e、7e 和 7g）具有低于 50 nM 的 IC 值，同时具有 VEGFR-2/Tie-2/EphB4 抑制活性。
