TY - JOUR
T1 - 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
AU - Powell, Jonathan
AU - Mota, Filipa
AU - Steadman, David
AU - Soudy, Christelle
AU - Miyauchi, Jeremy T.
AU - Crosby, Stuart
AU - Jarvis, Ashley
AU - Reisinger, Tifelle
AU - Winfield, Natalie
AU - Evans, Graham
AU - Finniear, Aled
AU - Yelland, Tamas
AU - Chou, Yi Tai
AU - Chan, A. W.Edith
AU - O'Leary, Andrew
AU - Cheng, Lili
AU - Liu, Dan
AU - Fotinou, Constantina
AU - Milagre, Carla
AU - Martin, John F.
AU - Jia, Haiyan
AU - Frankel, Paul
AU - Djordjevic, Snezana
AU - Tsirka, Stella E.
AU - Zachary, Ian C.
AU - Selwood, David L.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/5/10
Y1 - 2018/5/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85046817718
U2 - 10.1021/acs.jmedchem.8b00210
DO - 10.1021/acs.jmedchem.8b00210
M3 - Article
C2 - 29648813
AN - SCOPUS:85046817718
SN - 0022-2623
VL - 61
SP - 4135
EP - 4154
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -