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J Med Chem ; 61(9): 4135-4154, 2018 05 10.
Article in English | MEDLINE | ID: mdl-29648813

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 TGFß production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies.


Subject(s)
Immunomodulation/drug effects , Neuropilin-1/antagonists & inhibitors , Small Molecule Libraries/pharmacology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/biosynthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Design , Humans , Mice , Models, Molecular , Molecular Conformation , Pentanoic Acids/chemistry , Pentanoic Acids/pharmacology , Small Molecule Libraries/chemistry , T-Lymphocytes, Regulatory/immunology , Vascular Endothelial Growth Factor A/pharmacology
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