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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Apr 13

PMID 29648813

Citations 42

Authors

Jonathan Powell

Filipa Mota

David Steadman

Christelle Soudy

Jeremy T Miyauchi

Stuart Crosby

Ashley Jarvis

Tifelle Reisinger

Natalie Winfield

Graham Evans

Aled Finniear

Tamas Yelland

Yi-Tai Chou

A W Edith Chan

Andrew OLeary

Lili Cheng

Dan Liu

Constantina Fotinou

Carla Milagre

John F Martin

Haiyan Jia

Paul Frankel

Snezana Djordjevic

Stella E Tsirka

Ian C Zachary

David L Selwood

Affiliations

Soon will be listed here.

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.

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