NCE Discovery (Domainex Ltd) , Chesterford Research Park, Little Chesterford , Saffron Walden , Essex CB10 1XL , U.K.
The Wolfson Institute for Biomedical Research , University College London , Gower Street , London WC1E 6BT , U.K.
J Med Chem. 2018 May 10;61(9):4135-4154. doi: 10.1021/acs.jmedchem.8b00210. Epub 2018 Apr 24.
We report the design, synthesis, and biological evaluation of some potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumors, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229. The design of these molecules was informed and supported by X-ray crystal structures. Compound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays and was shown to have antiangiogenic, antimigratory, and antitumor effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1, FoxP3, and CD25 populations of Tregs from mice, 1 was able to block a glioma-conditioned medium-induced increase in TGFβ production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies.
我们报告了一些有效的小分子神经纤毛蛋白-1（NRP1）拮抗剂的设计、合成和生物学评价。NRP1 参与肿瘤的免疫反应，特别是在 Treg 细胞脆弱性中，这是 PD1 检查点阻断所必需的。这些化合物的设计基于先前鉴定的化合物 EG00229。这些分子的设计受到 X 射线晶体结构的启发和支持。化合物 1（EG01377）被确定为具有进一步研究的合适特性。然后，在几种体外测定中测试了化合物 1，并显示出具有抗血管生成、抗迁移和抗肿瘤作用。值得注意的是，1 被证明对 NRP1 具有选择性，而对密切相关的蛋白质 NRP2 则没有。在纯化的 Nrp1 中，来自小鼠的 FoxP3 和 CD25 群体的 Tregs 中，1 能够阻断神经胶质瘤条件培养基诱导的 TGFβ 产生增加。这种小分子 NRP1 拮抗剂的全面表征为未来的体内研究提供了基础。
