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Medchemcomm DOI:10.1039/c8md00297e

Novel tricyclic glycal-based inducers that reprogram LDL metabolism in hepatic cells.

Publication TypeJournal Article
Year of Publication2018
AuthorsNagiec, MM, Duvall, JR, Skepner, AP, Howe, EA, Bastien, J, Comer, E, Marie, J-C, Johnston, SE, Negri, J, Eichhorn, M, Vantourout, J, Clish, C, Musunuru, K, Foley, M, Perez, JR, Palmer, MAJ
Date Published2018 Nov 01

Increased expression of the Tribbles pseudokinase 1 gene () is associated with lower plasma levels of LDL cholesterol and triglycerides, higher levels of HDL cholesterol and decreased risk of coronary artery disease and myocardial infarction. We identified a class of tricyclic glycal core-based compounds that upregulate expression in human HepG2 cells and phenocopy the effects of genetic overexpression as they inhibit expression of triglyceride synthesis genes and ApoB secretion in cells. In addition to predicted effects related to downregulation of VLDL assembly and secretion these compounds also have unexpected effects as they upregulate expression of LDLR and stimulate LDL uptake. This activity profile is unique and favorably differs from profiles produced by statins or other lipoprotein targeting therapies. BRD8518, the initial lead compound from the tricyclic glycal class, exhibited stereochemically dependent activity and the potency far exceeding previously described benzofuran BRD0418. Gene expression profiling of cells treated with BRD8518 demonstrated the anticipated changes in lipid metabolic genes and revealed a broad stimulation of early response genes. Consistently, we found that BRD8518 activity is MEK1/2 dependent and the treatment of HepG2 cells with BRD8518 stimulates ERK1/2 phosphorylation. In agreement with down-regulation of genes controlling triglyceride synthesis and assembly of lipoprotein particles, the mass spectrometry analysis of cell extracts showed reduced rate of incorporation of stable isotope labeled glycerol into triglycerides in BRD8518 treated cells. Furthermore, we describe medicinal chemistry efforts that led to identification of BRD8518 analogs with enhanced potency and pharmacokinetic properties suitable for studies.


Alternate JournalMedchemcomm
PubMed ID30542533
PubMed Central IDPMC6247893