A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization

Cell Rep. 2019 Oct 1;29(1):62-75.e7. doi: 10.1016/j.celrep.2019.08.073.


Id helix-loop-helix (HLH) proteins (Id1-4) bind E protein bHLH transcription factors, preventing them from forming active transcription complexes that drive changes in cell states. Id proteins are primarily expressed during development to inhibit differentiation, but they become re-expressed in adult tissues in diseases of the vasculature and cancer. We show that the genetic loss of Id1/Id3 reduces ocular neovascularization in mouse models of wet age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). An in silico screen identifies AGX51, a small-molecule Id antagonist. AGX51 inhibits the Id1-E47 interaction, leading to ubiquitin-mediated degradation of Ids, cell growth arrest, and reduced viability. AGX51 is well-tolerated in mice and phenocopies the genetic loss of Id expression in AMD and ROP models by inhibiting retinal neovascularization. Thus, AGX51 is a first-in-class compound that antagonizes an interaction formerly considered undruggable and that may have utility in the management of multiple diseases.

Keywords: Id proteins; angiogenesis; macular degeneration; protein-protein interactions; retinopathy of prematurity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • HCT116 Cells
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inhibitor of Differentiation Protein 1 / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / metabolism
  • Small Molecule Libraries / pharmacology*


  • Basic Helix-Loop-Helix Transcription Factors
  • Inhibitor of Differentiation Protein 1
  • Small Molecule Libraries