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Publication Detail
Small molecule neuropilin-1 antagonists combine anti-angiogenic and anti-tumour activity with immune modulation through reduction of transforming growth factor beta (TGFβ) production in regulatory T-cells.
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Powell J, Mota F, Steadman D, Soudy C, Miyauchi JT, Crosby S, Jarvis A, Reisinge T, Winfield N, Evans G, Finniear A, Yelland T, Chou Y-T, Chan AWE, O'Leary A, Cheng L, Liu D, Fotinou N, Milagre C, Martin JF, Jia H, Frankel P, Djordjevic S, Tsirka SE, Zachary IC, Selwood DL
  • Publication date:
  • Journal:
    Journal of medicinal chemistry
  • Medium:
  • Status:
  • Print ISSN:
  • Language:
We report the design, synthesis and comprehensive studybiological evaluation of a range ofsome potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumours, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229, EG00229 which was used a starting point for optimisation. Through targeting of specific amino-acid residues additional H-bonding interactions were introduced, which led to increases in binding affinity and potency. The design of these molecules was informed and supported by X-ray crystal structures. Pharmacokinetic data was obtained for some of the most potent compounds, and cCompound 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 anti-angiogenic, anti-migratory and anti-tumour effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, CD25+ populations of Tregs from mice 1 was able to block a glioma conditioned medium induced increase in TGFβ production. This study therefore represents a comprehensive characterisation of a small-molecule NRP1 antagonist, and provides the basis for future in vivo studies.
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