6J3P

Crystal structure of the human GCN5 bromodomain in complex with compound (R,R)-36n

Summary for 6J3P

• Entry DOI: 10.2210/pdb6j3p/pdb
• Descriptor: Histone acetyltransferase KAT2A, 2-{[(3R,5R)-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-methylpiperidin-3-yl]amino}-3-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (3 entities in total)
• Functional Keywords: crystal structure of the human gcn5 bromodomain in complex with compound (r, r)-36n, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 32793.55

Authors

Huang, L.Y.,Li, H.,Niu, L.,Wu, C.Y.,Yu, Y.M.,Li, L.L.,Yang, S.Y. (deposition date: 2019-01-05, release date: 2019-05-01, Last modification date: 2023-11-22)

Primary citation

Huang, L.,Li, H.,Li, L.,Niu, L.,Seupel, R.,Wu, C.,Cheng, W.,Chen, C.,Ding, B.,Brennan, P.E.,Yang, S.
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.
J.Med.Chem., 62:4526-4542, 2019

PubMed 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 IC of 7 nM in homogeneous time-resolved fluorescence assay and a K 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.

PubMed: 30998845
DOI: 10.1021/acs.jmedchem.9b00096

Experimental method

X-RAY DIFFRACTION (1.598 Å)