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


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.

SUBMITTER: Wojnarowicz PM 

PROVIDER: S-EPMC6896334 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Wojnarowicz Paulina M PM   Lima E Silva Raquel R   Ohnaka Masayuki M   Lee Sang Bae SB   Chin Yvette Y   Kulukian Anita A   Chang Sung-Hee SH   Desai Bina B   Garcia Escolano Marta M   Shah Riddhi R   Garcia-Cao Marta M   Xu Sijia S   Kadam Rashmi R   Goldgur Yehuda Y   Miller Meredith A MA   Ouerfelli Ouathek O   Yang Guangli G   Arakawa Tsutomu T   Albanese Steven K SK   Garland William A WA   Stoller Glenn G   Chaudhary Jaideep J   Norton Larry L   Soni Rajesh Kumar RK   Philip John J   Hendrickson Ronald C RC   Iavarone Antonio A   Dannenberg Andrew J AJ   Chodera John D JD   Pavletich Nikola N   Lasorella Anna A   Campochiaro Peter A PA   Benezra Robert R  

Cell reports 20191001 1


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 retino  ...[more]

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