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

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

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Departments of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
4
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
5
Structural Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Alliance Protein Laboratories, a Division of KBI Biopharma, San Diego, CA 92121, USA.
8
Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Tosk, Inc., Mountain View, CA 94043, USA.
10
Ophthalmic Consultants of Long Island, Lynbrook, NY 11563, USA.
11
Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA.
12
Evelyn H. Lauder Breast Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
13
Proteomics & Microchemistry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
14
Department of Neurology, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
15
Department of Pediatrics, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
16
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: benezrar@mskcc.org.

Abstract

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

PMID:
31577956
DOI:
10.1016/j.celrep.2019.08.073
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