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Merck

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

Cell reports (2019-10-03)
Paulina M Wojnarowicz, Raquel Lima E Silva, Masayuki Ohnaka, Sang Bae Lee, Yvette Chin, Anita Kulukian, Sung-Hee Chang, Bina Desai, Marta Garcia Escolano, Riddhi Shah, Marta Garcia-Cao, Sijia Xu, Rashmi Kadam, Yehuda Goldgur, Meredith A Miller, Ouathek Ouerfelli, Guangli Yang, Tsutomu Arakawa, Steven K Albanese, William A Garland, Glenn Stoller, Jaideep Chaudhary, Larry Norton, Rajesh Kumar Soni, John Philip, Ronald C Hendrickson, Antonio Iavarone, Andrew J Dannenberg, John D Chodera, Nikola Pavletich, Anna Lasorella, Peter A Campochiaro, Robert Benezra
要旨

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.

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Sigma-Aldrich
モノクローナル抗FLAG® M2抗体 マウス宿主抗体, 1 mg/mL, clone M2, affinity isolated antibody, buffered aqueous solution (50% glycerol, 10 mM sodium phosphate, and 150 mM NaCl, pH 7.4)
Sigma-Aldrich
ジギトニン, Used as non-ionic detergent
Sigma-Aldrich
モノクロナール抗β-アクチン マウス宿主抗体, clone AC-15, ascites fluid
Sigma-Aldrich
モノクローナル抗ビンキュリン抗体 マウス宿主抗体, clone hVIN-1, ascites fluid
Sigma-Aldrich
抗アクチン ウサギ宿主抗体, affinity isolated antibody, buffered aqueous solution
Millipore
EZview Red 抗FLAG®M2抗体 アフィニティーゲル, clone M2
Sigma-Aldrich
モノクロナール抗β-チューブリン マウス宿主抗体, clone TUB 2.1, ascites fluid
Sigma-Aldrich
Z-Leu-Leu-Leu-al, ≥90% (HPLC)
Sigma-Aldrich
AGX51, ≥98% (HPLC)