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

  • J Med Chem. 2018 May 10;61(9):4135-4154. doi: 10.1021/acs.jmedchem.8b00210.
Jonathan Powell  1 ,  Filipa Mota  2 ,  David Steadman  2 ,  Christelle Soudy  2 ,  Jeremy T Miyauchi  3 ,  Stuart Crosby  1 ,  Ashley Jarvis  1 ,  Tifelle Reisinger  1 ,  Natalie Winfield  1 ,  Graham Evans  4 ,  Aled Finniear  4 ,  Tamas Yelland ,  Yi-Tai Chou  2 ,  A W Edith Chan  2 ,  Andrew O'Leary  5 ,  Lili Cheng  5 ,  Dan Liu  5 ,  Constantina Fotinou  6 ,  Carla Milagre  5 ,  John F Martin  5 ,  Haiyan Jia  5 ,  Paul Frankel  5 ,  Snezana Djordjevic  6 ,  Stella E Tsirka  3 ,  Ian C Zachary  5 ,  David L Selwood  2
Affiliations
  • 1. NCE Discovery (Domainex Ltd) , Chesterford Research Park, Little Chesterford , Saffron Walden , Essex CB10 1XL , U.K.
  • 2. The Wolfson Institute for Biomedical Research , University College London , Gower Street , London WC1E 6BT , U.K.
  • 3. Department of Pharmacology , Stony Brook University , Stony Brook , New York 11794 , United States.
  • 4. Park Place Research Ltd , Unit 5/6 Willowbrook Technology Park, Llandogo Road, St. Mellons , Cardiff CF3 0EF , U.K.
  • 5. Centre for Cardiovascular Biology and Medicine, Division of Medicine , University College London , 5 University Street , London WC1E 6JJ , U.K.
  • 6. Institute of Structural and Molecular Biology , University College London , Gower Street , London WC1E 6BT , U.K.
PMID: 29648813 DOI: 10.1021/acs.jmedchem.8b00210
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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