title: Discovery of a new molecular probe ML228: an activator of the hypoxia inducible factor (HIF) pathway.
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.
authors.affiliation: The Broad Institute Probe Development Center, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Jimmy R
authors.initials: JR
authors.lastname: Theriault
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Felts
authors.forename: Brittney S
authors.initials: BS
authors.lastname: Bates
authors.forename: Jose R
authors.initials: JR
authors.lastname: Perez
authors.forename: Michelle
authors.initials: M
authors.lastname: Palmer
authors.forename: Shawn R
authors.initials: SR
authors.lastname: Gilbert
authors.forename: Eric S
authors.initials: ES
authors.lastname: Dawson
authors.forename: Julie L
authors.initials: JL
authors.lastname: Engers
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Emmitte
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008956:Models, Chemical; D008968:Molecular Conformation; D015335:Molecular Probes / Q000494:pharmacology*; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; C573773:ML228 probe; D015335:Molecular Probes; D011725:Pyridines; D014227:Triazines; D042461:Vascular Endothelial Growth Factor A