Discovery of a new molecular probe ML228: an activator of the hypoxia inducible factor (HIF) pathway.
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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. |
Year of Publication | 2012
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Journal | Bioorg Med Chem Lett
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Volume | 22
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Issue | 1
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Pages | 76-81
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Date Published | 2012 Jan 01
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ISSN | 1464-3405
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URL | |
DOI | 10.1016/j.bmcl.2011.11.077
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PubMed ID | 22172704
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PubMed Central ID | PMC3251333
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Grant list | 1U54HG005032-01 / HG / NHGRI NIH HHS / United States
U54 HG005032-01 / HG / NHGRI NIH HHS / United States
U54 MH084659 / MH / NIMH NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
R03 MH082355 / MH / NIMH NIH HHS / United States
1U54MH084659-01 / MH / NIMH NIH HHS / United States
U54 MH084659-01 / MH / NIMH NIH HHS / United States
R03 MH082355-01A2 / MH / NIMH NIH HHS / United States
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