Target structure-based discovery of small molecules that block human p53 and CREB binding protein association.
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.
Sachchidanand
Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York 10029, USA.
Resnick-Silverman
Lois
L
Yan
Sherry
S
Mutjaba
Shiraz
S
Liu
Wen-Jun
WJ
Zeng
Lei
L
Manfredi
James J
JJ
Zhou
Ming-Ming
MM
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
D008024:Ligands; D016159:Tumor Suppressor Protein p53; D050882:CREB-Binding Protein