April 2009
Volume 50, Issue 13
ARVO Annual Meeting Abstract  |   April 2009
A Novel Class of Small Molecules for Treatment of Retinopathy of Prematurity
Author Affiliations & Notes
  • G. Hoppe
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • Q. Ebrahem
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • J. E. Sears
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • Footnotes
    Commercial Relationships  G. Hoppe, None; Q. Ebrahem, None; J.E. Sears, None.
  • Footnotes
    Support  Research to Prevent Blindness Challenge Grant, Cleveland Clinic Product Development Fund, Knights Templar Eye Foundation.
Investigative Ophthalmology & Visual Science April 2009, Vol.50, 3126. doi:
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      G. Hoppe, Q. Ebrahem, J. E. Sears; A Novel Class of Small Molecules for Treatment of Retinopathy of Prematurity. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3126.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : To expand the search for a pharmaceutical treatment of retinopathy of prematurity based on our recent observation of preventing oxygen induced vascular obliteration by activation of hypoxia inducible factor 1 (HIF-1). In this study we have conducted high throughput large scale screening of the Chembridge small molecule library for compounds capable of upregulating HIF-1.

Methods: : A Chemical DiverSet library of 34,000 chemical compounds consisted of handcrafted drug-like organic molecules with molecular weight in a range of 250 - 550. Primary screening was performed using NIH3T3 cell line stably expressing reporter gene of firefly luciferase under a HIF-1-inducible promoter. Hierarchical multi-step validation of the reporter gene activators was performed by assessing their effect on endogenous HIF-1 levels and erythropoietin (Epo) secretion in cell cultures.

Results: : We have identified and selected 23 potential HIF inducers that demonstrate ability to stimulate HIF-dependent transcription at list 3-fold. Six compounds increased Epo protein levels while only four compounds substantially induced HIF-1 levels in cultured cells. One compound lead to HIF-1 upregulation that did not lead to Epo expression and three other compounds caused Epo production, but only minimal induction of HIF-1. As a result of secondary screening we have selected 3 compounds that induce robust increase of intracellular HIF-1 and secreted Epo by cultures cells.

Conclusions: : A striking number of compounds capable of HIF-1 upregulation were from a similar family of small molecules. Furthermore, newly identified HIF activators were potent at relatively low micromolar concentrations. Finally, their differential effects on HIF and Epo induction provide us with a molecular tool to dissect the pathways involved in the protection of the neurovascular unit.

Keywords: retinopathy of prematurity • hypoxia • transcription factors 

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