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Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFβ) Production in Regulatory T-Cells.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-04-24 , DOI: 10.1021/acs.jmedchem.8b00210
Jonathan Powell 1 , Filipa Mota 2 , David Steadman 2 , Christelle Soudy 2 , Jeremy T Miyauchi 3 , Stuart Crosby 1 , Ashley Jarvis 1 , Tifelle Reisinger 1 , Natalie Winfield 1 , Graham Evans 4 , Aled Finniear 4 , Tamas Yelland , Yi-Tai Chou 2 , A W Edith Chan 2 , Andrew O'Leary 5 , Lili Cheng 5 , Dan Liu 5 , Constantina Fotinou 6 , Carla Milagre 5 , John F Martin 5 , Haiyan Jia 5 , Paul Frankel 5 , Snezana Djordjevic 6 , Stella E Tsirka 3 , Ian C Zachary 5 , David L Selwood 2
Affiliation  

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.

中文翻译:

小分子 Neuropilin-1 拮抗剂通过减少调节性 T 细胞中转化生长因子 β (TGFβ) 的产生,将抗血管生成和抗肿瘤活性与免疫调节相结合。

我们报告了一些有效的小分子神经纤维蛋白-1 (NRP1) 拮抗剂的设计、合成和生物学评价。NRP1 与对肿瘤的免疫反应有关,特别是在 Treg 细胞的脆性中,这是 PD1 检查点阻断所必需的。这些化合物的设计基于先前确定的化合物 EG00229。这些分子的设计由 X 射线晶体结构提供信息和支持。化合物 1 (EG01377) 被鉴定为具有适合进一步研究的特性。然后在几个体外试验中测试了化合物 1,并显示其具有抗血管生成、抗迁移和抗肿瘤作用。值得注意的是,1 被证明对 NRP1 的选择性高于密切相关的蛋白质 NRP2。在纯化的 Nrp1+、FoxP3+ 和 CD25+ 小鼠 Treg 群中,1能够阻断胶质瘤条件培养基诱导的TGFβ产生增加。小分子 NRP1 拮抗剂的这种全面表征为未来的体内研究奠定了基础。
更新日期:2018-04-12
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