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

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 hy...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.76-81
Main Authors: Theriault, Jimmy R., Felts, Andrew S., Bates, Brittney S., Perez, Jose R., Palmer, Michelle, Gilbert, Shawn R., Dawson, Eric S., Engers, Julie L., Lindsley, Craig W., Emmitte, Kyle A.
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Biological and medical sciences
cardiovascular diseases
chemistry
Chemistry, Pharmaceutical - methods
chemotypes
Dose-Response Relationship, Drug
Drug Design
HIF
Humans
Hypoxia
Hypoxia - drug therapy
Hypoxia-Inducible Factor 1 - metabolism
Ischemia
Medical sciences
Models, Chemical
Molecular Conformation
Molecular Probes - pharmacology
Neovascularization, Pathologic
oxygen
Pharmacology. Drug treatments
Protein Structure, Tertiary
proteins
public health
Pyridines - chemical synthesis
Pyridines - pharmacology
reporter genes
Structure-Activity Relationship
transcription factors
Triazine
triazines
Triazines - chemical synthesis
Triazines - chemistry
Triazines - pharmacology
Vascular Endothelial Growth Factor A - metabolism
VEGF
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Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.11.077