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Start Over Author "Magnuson SR" Publisher elsevier science ltd
2 results on '"Magnuson SR"'

1. Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance.

Author

Crawford TD, Vartanian S, Côté A, Bellon S, Duplessis M, Flynn EM, Hewitt M, Huang HR, Kiefer JR, Murray J, Nasveschuk CG, Pardo E, Romero FA, Sandy P, Tang Y, Taylor AM, Tsui V, Wang J, Wang S, Zawadzke L, Albrecht BK, Magnuson SR, Cochran AG, and Stokoe D

Subjects
Aldehyde Dehydrogenase genetics, Aldehyde Dehydrogenase 1 Family, Cell Line, Tumor, Drug Design, Drug Resistance, Neoplasm drug effects, Humans, Molecular Docking Simulation, Pyridones chemistry, Pyridones pharmacology, Retinal Dehydrogenase, Transcription Factors metabolism, Drug Resistance drug effects, Epigenesis, Genetic drug effects, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Transcription Factors antagonists & inhibitors
Abstract

Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Published
2017
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2. Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors.

Author

Wang L, Stanley M, Boggs JW, Crawford TD, Bravo BJ, Giannetti AM, Harris SF, Magnuson SR, Nonomiya J, Schmidt S, Wu P, Ye W, Gould SE, Murray LJ, Ndubaku CO, and Chen H

Subjects
Animals, Crystallography, X-Ray, Dose-Response Relationship, Drug, Humans, Intracellular Signaling Peptides and Proteins metabolism, Ligands, Mice, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases metabolism, Structure-Activity Relationship, Triazines chemical synthesis, Triazines chemistry, NF-kappaB-Inducing Kinase, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Triazines pharmacology
Abstract

MAP4K4 has been shown to regulate key cellular processes that are tied to disease pathogenesis. In an effort to generate small molecule MAP4K4 inhibitors, a fragment-based screen was carried out and a pyrrolotriazine fragment with excellent ligand efficiency was identified. Further modification of this fragment guided by X-ray crystal structures and molecular modeling led to the discovery of a series of promising compounds with good structural diversity and physicochemical properties. These compounds exhibited single digit nanomolar potency and compounds 35 and 44 achieved good in vivo exposure., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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