@article{
 title = {Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands},
 type = {article},
 year = {2013},
 keywords = {Acetylation,CREB-Binding Protein,CREB-Binding Protein: metabolism,Cell Line,Crystallography,Histones,Histones: metabolism,Humans,Inhibitory Concentration 50,Isoxazoles,Isoxazoles: chemical synthesis,Isoxazoles: chemistry,Isoxazoles: pharmacology,Ligands,Lysine,Lysine: metabolism,Nuclear Proteins,Nuclear Proteins: antagonists & inhibitors,Nuclear Proteins: chemistry,Protein Binding,Structure-Activity Relationship,Transcription Factors,Transcription Factors: antagonists & inhibitors,Transcription Factors: chemistry,Tumor,X-Ray},
 pages = {3217-3227},
 volume = {56},
 websites = {http://dx.doi.org/10.1021/jm301588r,http://pubs.acs.org/doi/pdfplus/10.1021/jm301588r},
 publisher = {American Chemical Society},
 id = {57c47b0b-cadc-37ad-be67-b48262975e18},
 created = {2015-10-07T14:20:50.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:48.802Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hewings2013},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.},
 bibtype = {article},
 author = {Hewings, David S. and Fedorov, Oleg and Filippakopoulos, Panagis and Martin, Sarah and Picaud, Sarah and Tumber, Anthony and Wells, Christopher and Olcina, Monica M. and Freeman, Katherine and Gill, Andrew and Ritchie, Alison J. and Sheppard, David W. and Russell, Angela J. and Hammond, Ester M. and Knapp, Stefan and Brennan, Paul E. and Conway, Stuart J.},
 doi = {10.1021/jm301588r},
 journal = {Journal of Medicinal Chemistry},
 number = {8}
}

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Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.","bibtype":"article","author":"Hewings, David S. and Fedorov, Oleg and Filippakopoulos, Panagis and Martin, Sarah and Picaud, Sarah and Tumber, Anthony and Wells, Christopher and Olcina, Monica M. and Freeman, Katherine and Gill, Andrew and Ritchie, Alison J. and Sheppard, David W. and Russell, Angela J. and Hammond, Ester M. and Knapp, Stefan and Brennan, Paul E. and Conway, Stuart J.","doi":"10.1021/jm301588r","journal":"Journal of Medicinal Chemistry","number":"8","bibtex":"@article{\n title = {Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands},\n type = {article},\n year = {2013},\n keywords = {Acetylation,CREB-Binding Protein,CREB-Binding Protein: metabolism,Cell Line,Crystallography,Histones,Histones: metabolism,Humans,Inhibitory Concentration 50,Isoxazoles,Isoxazoles: chemical synthesis,Isoxazoles: chemistry,Isoxazoles: pharmacology,Ligands,Lysine,Lysine: metabolism,Nuclear Proteins,Nuclear Proteins: antagonists & inhibitors,Nuclear Proteins: chemistry,Protein Binding,Structure-Activity Relationship,Transcription Factors,Transcription Factors: antagonists & inhibitors,Transcription Factors: chemistry,Tumor,X-Ray},\n pages = {3217-3227},\n volume = {56},\n websites = {http://dx.doi.org/10.1021/jm301588r,http://pubs.acs.org/doi/pdfplus/10.1021/jm301588r},\n publisher = {American Chemical Society},\n id = {57c47b0b-cadc-37ad-be67-b48262975e18},\n created = {2015-10-07T14:20:50.000Z},\n file_attached = {true},\n profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},\n last_modified = {2018-07-09T12:39:48.802Z},\n read = {false},\n starred = {false},\n authored = {true},\n confirmed = {true},\n hidden = {false},\n citation_key = {Hewings2013},\n source_type = {Journal Article},\n private_publication = {false},\n abstract = {The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. 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