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.
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.
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DOI：
10.1021/acs.jmedchem.8b00210
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发表时间：
2018-05-10
影响因子：
7.3
通讯作者：
Selwood DL
中科院分区：
文献类型：
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作者：
Powell J;Mota F;Steadman D;Soudy C;Miyauchi JT;Crosby S;Jarvis A;Reisinger T;Winfield N;Evans G;Finniear A;Yelland T;Chou YT;Chan AWE;O'Leary A;Cheng L;Liu D;Fotinou C;Milagre C;Martin JF;Jia H;Frankel P;Djordjevic S;Tsirka SE;Zachary IC;Selwood DL
我们报道了一些有效的小分子神经匹林-1 （NRP1）拮抗剂的设计、合成和生物学评价。NRP1与肿瘤的免疫应答有关，特别是在PD1检查点阻断所需的Treg细胞脆弱性中。这些化合物的设计基于先前鉴定的化合物EG00229。这些分子的设计是由x射线晶体结构提供信息和支持的。化合物1 （EG01377）具有适合进一步研究的性质。化合物1随后在几种体外实验中进行了测试，并显示出抗血管生成、抗迁移和抗肿瘤的作用。值得注意的是，1被证明对NRP1具有选择性，而不是密切相关的NRP2蛋白。在纯化的Nrp1+、FoxP3+和CD25+小鼠treg群体中，1能够阻断胶质瘤条件培养基诱导的tgf - β产生的增加。这种小分子NRP1拮抗剂的综合表征为未来的体内研究提供了基础。
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.
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影响因子：
4.7
作者：
Graziani G;Lacal PM
通讯作者：
Lacal PM
影响因子：
8
作者：
Grun D;Adhikary G;Eckert RL
通讯作者：
Eckert RL
影响因子：
4.8
作者：
Jia, HY;Bagherzadeh, A;Zachary, IC
通讯作者：
Zachary, IC
影响因子：
5.5
作者：
Glinka, Yelena;Prud'homme, Gerald J.
通讯作者：
Prud'homme, Gerald J.
DOI：
10.1107/s090744499900935x
发表时间：
1999-10-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Pflugrath, JW
通讯作者：
Pflugrath, JW