Discovery of a PCAF Bromodomain Chemical Probe

Discovery of a PCAF Bromodomain Chemical Probe. Moustakim, M., Clark, P., G., Trulli, L., Fuentes de Arriba, A., L., Ehebauer, M., T., Chaikuad, A., Murphy, E., J., Mendez-Johnson, J., Daniels, D., Hou, C., F., D., Lin, Y., H., Walker, J., R., Hui, R., Yang, H., Dorrell, L., Rogers, C., M., Monteiro, O., P., Fedorov, O., Huber, K., V., Knapp, S., Heer, J., Dixon, D., J., & Brennan, P., E. Angewandte Chemie - International Edition, 56(3):827-831, 1, 2017.

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Discovery of a PCAF Bromodomain Chemical Probe [link]

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The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl trans- ferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(?)-nor- ephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falci- parum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cyto- toxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use. Bromodomains

@article{
 title = {Discovery of a PCAF Bromodomain Chemical Probe},
 type = {article},
 year = {2017},
 keywords = {bromodomains,chemical probes,epigenetics,medicinal chemistry,structure-based design},
 pages = {827-831},
 volume = {56},
 websites = {http://doi.wiley.com/10.1002/anie.201610816},
 month = {1},
 day = {16},
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 created = {2017-01-23T19:27:38.000Z},
 accessed = {2017-01-23},
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 last_modified = {2024-04-10T13:28:05.397Z},
 read = {true},
 starred = {true},
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 citation_key = {Moustakim2017},
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 abstract = {The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl trans- ferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(?)-nor- ephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falci- parum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cyto- toxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use. Bromodomains},
 bibtype = {article},
 author = {Moustakim, Moses and Clark, Peter G.K. and Trulli, Laura and Fuentes de Arriba, Angel L. and Ehebauer, Matthias T. and Chaikuad, Apirat and Murphy, Emma J. and Mendez-Johnson, Jacqui and Daniels, Danette and Hou, Chun Feng D. and Lin, Yu Hui and Walker, John R. and Hui, Raymond and Yang, Hongbing and Dorrell, Lucy and Rogers, Catherine M. and Monteiro, Octovia P. and Fedorov, Oleg and Huber, Kilian V.M. and Knapp, Stefan and Heer, Jag and Dixon, Darren J. and Brennan, Paul E.},
 doi = {10.1002/anie.201610816},
 journal = {Angewandte Chemie - International Edition},
 number = {3}
}

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