6FMC
Neuropilin1-b1 domain in complex with EG01377, 0.9 Angstrom structure
Summary for 6FMC
| Entry DOI | 10.2210/pdb6fmc/pdb |
| Descriptor | Neuropilin-1, (2~{S})-2-[[3-[[5-[4-(aminomethyl)phenyl]-1-benzofuran-7-yl]sulfonylamino]thiophen-2-yl]carbonylamino]-5-carbamimidamido-pentanoic acid (3 entities in total) |
| Functional Keywords | vegf-receptor, semaphorin-receptor, small molecule inhibitor, angiogenesis, discoidin domain, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 18501.96 |
| Authors | Yelland, T.,Djordjevic, S.,Fotinou, K.,Selwood, D.,Zachary, I.,Frankel, P. (deposition date: 2018-01-30, release date: 2018-10-17, Last modification date: 2024-10-23) |
| Primary citation | Powell, J.,Mota, F.,Steadman, D.,Soudy, C.,Miyauchi, J.T.,Crosby, S.,Jarvis, A.,Reisinger, T.,Winfield, N.,Evans, G.,Finniear, A.,Yelland, T.,Chou, Y.T.,Chan, A.W.E.,O'Leary, A.,Cheng, L.,Liu, D.,Fotinou, C.,Milagre, C.,Martin, J.F.,Jia, H.,Frankel, P.,Djordjevic, S.,Tsirka, S.E.,Zachary, I.C.,Selwood, D.L. Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGF beta ) Production in Regulatory T-Cells. J. Med. Chem., 61:4135-4154, 2018 Cited by PubMed Abstract: 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. PubMed: 29648813DOI: 10.1021/acs.jmedchem.8b00210 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (0.9 Å) |
Structure validation
Download full validation report
