Discovery of a new molecular probe ML228: An activator of the hypoxia inducible factor (HIF) pathway

Jimmy R. Theriault, Andrew S. Felts, Brittney S. Bates, Jose R. Perez, Michelle Palmer, Shawn R. Gilbert, Eric S. Dawson, Julie L. Engers, Craig W. Lindsley, Kyle A. Emmitte

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14 Scopus citations

Abstract

Hypoxia and ischemia are linked to several serious public health problems that affect most major organ systems. Specific examples include diseases of the cardiovascular, pulmonary, renal, neurologic, and musculoskeletal systems. The most significant pathway for cellular response to hypoxia is the hypoxia inducible factor (HIF) pathway. HIFs are transcription factors responsible for the activation of genes which encode proteins that mediate adaptive responses to reduced oxygen availability. A high-throughput cell-based HIF-mediated gene reporter screen was carried out using the NIH's Molecular Libraries Small Molecule Repository to identify activators of the HIF pathway. This communication describes the subsequent medicinal chemistry optimization of a triazine scaffold that led to the identification of the new molecular probe ML228. A discussion of HIF activation SAR within this chemotype as well as detailed in vitro characterization of the probe molecule is presented here.

Original languageEnglish
Pages (from-to)76-81
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number1
DOIs
StatePublished - 1 Jan 2012

Keywords

  • Angiogenesis
  • HIF
  • Hypoxia
  • Ischemia
  • Triazine
  • VEGF

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    Theriault, J. R., Felts, A. S., Bates, B. S., Perez, J. R., Palmer, M., Gilbert, S. R., Dawson, E. S., Engers, J. L., Lindsley, C. W., & Emmitte, K. A. (2012). Discovery of a new molecular probe ML228: An activator of the hypoxia inducible factor (HIF) pathway. Bioorganic and Medicinal Chemistry Letters, 22(1), 76-81. https://doi.org/10.1016/j.bmcl.2011.11.077