Discovery of Pyrrolo[3,2- d]pyrimidin-4-one Derivatives as a New Class of Potent and Cell-Active Inhibitors of P300/CBP-Associated Factor Bromodomain

Discovery of Pyrrolo[3,2- d]pyrimidin-4-one Derivatives as a New Class of Potent and Cell-Active Inhibitors of P300/CBP-Associated Factor Bromodomain. Huang, L., Li, H., Li, L., Niu, L., Seupel, R., Wu, C., Cheng, W., Chen, C., Ding, B., Brennan, P., E., & Yang, S. Journal of Medicinal Chemistry, 62(9):4526-4542, American Chemical Society, 4, 2019.

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Herein, we report the discovery of a series of new P300/CBP-associated factor (PCAF) bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activity relationship analyses toward a retrieved hit compound (12). Among these inhibitors, (R,R)-36n is the most potent one with an IC50 of 7 nM in homogeneous time-resolved fluorescence assay and a KD of 78 nM in isothermal titration calorimetry assay. This compound also exhibited activity against GCN5 and FALZ, but weak or no activity against other 29 BRD proteins and 422 kinases, indicating considerable selectivity. X-ray cocrystal structure analysis revealed the molecular interaction mode and the precise stereochemistry required for bioactivity. Cellular activity, preliminary RNA-seq analysis, and pharmacokinetic properties were also examined for this compound. Collectively, this study provides a versatile tool molecule to explore molecular mechanisms of PCAF BRD regulation and also offers a new lead compound for drug discovery targeting PCAF.

@article{
 title = {Discovery of Pyrrolo[3,2- d]pyrimidin-4-one Derivatives as a New Class of Potent and Cell-Active Inhibitors of P300/CBP-Associated Factor Bromodomain},
 type = {article},
 year = {2019},
 pages = {4526-4542},
 volume = {62},
 websites = {http://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00096},
 month = {4},
 publisher = {American Chemical Society},
 day = {18},
 id = {093bf831-f9bf-3ae2-9e2e-b872f14c569f},
 created = {2019-04-25T07:16:01.164Z},
 accessed = {2019-04-25},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2020-08-18T17:56:43.890Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Huang2019},
 private_publication = {false},
 abstract = {Herein, we report the discovery of a series of new P300/CBP-associated factor (PCAF) bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activity relationship analyses toward a retrieved hit compound (12). Among these inhibitors, (R,R)-36n is the most potent one with an IC50 of 7 nM in homogeneous time-resolved fluorescence assay and a KD of 78 nM in isothermal titration calorimetry assay. This compound also exhibited activity against GCN5 and FALZ, but weak or no activity against other 29 BRD proteins and 422 kinases, indicating considerable selectivity. X-ray cocrystal structure analysis revealed the molecular interaction mode and the precise stereochemistry required for bioactivity. Cellular activity, preliminary RNA-seq analysis, and pharmacokinetic properties were also examined for this compound. Collectively, this study provides a versatile tool molecule to explore molecular mechanisms of PCAF BRD regulation and also offers a new lead compound for drug discovery targeting PCAF.},
 bibtype = {article},
 author = {Huang, Lu-Yi and Li, Hui and Li, Lin-Li and Niu, Lu and Seupel, Raina and Wu, Chengyong and Cheng, Wei and Chen, Chong and Ding, Bisen and Brennan, Paul E and Yang, Shengyong},
 doi = {10.1021/acs.jmedchem.9b00096},
 journal = {Journal of Medicinal Chemistry},
 number = {9}
}

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