title: Target structure-based discovery of small molecules that block human p53 and CREB binding protein association.
abstract: Lysine acetylation of human tumor suppressor p53 in response to cellular stress signals is required for its function as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report small molecules that block lysine 382-acetylated p53 association with the bromodomain of the coactivator CBP, an interaction essential for p53-induced transcription of the cell cycle inhibitor p21 in response to DNA damage. These chemicals were discovered in target structure-guided nuclear magnetic resonance spectroscopy screening of a focused chemical library constructed based on the structural knowledge of CBP bromodomain/p53-AcK382 binding. Structural characterization shows that these chemicals inhibit CBP/p53 association by binding to the acetyl-lysine binding site of the bromodomain. Cell-based functional assays demonstrate that the lead chemicals can modulate p53 stability and function in response to DNA damage.
authors.affiliation: Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York 10029, USA.
authors.lastname: Sachchidanand
authors.forename: Lois
authors.initials: L
authors.lastname: Resnick-Silverman
authors.forename: Sherry
authors.initials: S
authors.lastname: Yan
authors.forename: Shiraz
authors.initials: S
authors.lastname: Mutjaba
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.forename: James J
authors.initials: JJ
authors.lastname: Manfredi
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
mesh_terms: D001665:Binding Sites; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008970:Molecular Weight; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D016159:Tumor Suppressor Protein p53; D050882:CREB-Binding Protein