6fmc
Neuropilin1-b1 domain in complex with EG01377, 0.9 Angstrom structure
Structural highlights
FunctionNRP1_HUMAN The membrane-bound isoform 1 is a receptor involved in the development of the cardiovascular system, in angiogenesis, in the formation of certain neuronal circuits and in organogenesis outside the nervous system. It mediates the chemorepulsant activity of semaphorins. It binds to semaphorin 3A, The PLGF-2 isoform of PGF, The VEGF-165 isoform of VEGF and VEGF-B. Coexpression with KDR results in increased VEGF-165 binding to KDR as well as increased chemotaxis. It may regulate VEGF-induced angiogenesis. The soluble isoform 2 binds VEGF-165 and appears to inhibit its binding to cells. It may also induce apoptosis by sequestering VEGF-165. May bind as well various members of the semaphorin family. Its expression has an averse effect on blood vessel number and integrity. Publication Abstract from PubMedWe 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 TGFbeta production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies. Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFbeta) Production in Regulatory T-Cells.,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 J Med Chem. 2018 May 10;61(9):4135-4154. doi: 10.1021/acs.jmedchem.8b00210. Epub , 2018 Apr 24. PMID:29648813[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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