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

Journal article

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.

Authors: Huang, L; Li, H; Li, L; Niu, L; Seupel, R

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Journal of Medicinal Chemistry
• Volume: 62
• Issue: 9
• Pages: 4526-4542
• Publication date: 2019-04-30
• Acceptance date: 2019-04-18
• DOI: 10.1021/acs.jmedchem.9b00096
• EISSN: 1520-4804
• ISSN: 0022-2623
• Pmid: 30998845
• Language: English
• Keywords: FFR