期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 9, 页码 4135-4154出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00210
关键词
-
资金
- BHF [RG/11/11/29050]
- Ark Therapeutics
- Magnus Life Ltd.
- NIH [F30CA196110, R01NS42168]
- EPSRC [EP/P020410/1, EP/K005030/1] Funding Source: UKRI
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 PDI 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 Nrp14, FoxP34, and CD254 populations of Tregs from mice, 1 was able to block a glioma-conditioned medium-induced increase in TGFfl production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据