Target structure-based discovery of small molecules that block human p53 and CREB binding protein association

Sachchidanand, Lois Resnick-Silverman, Sherry Yan, Shiraz Mutjaba, Wen Jun Liu, Lei Zeng, James J. Manfredi, Ming Ming Zhou

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

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.

Original languageEnglish
Pages (from-to)81-90
Number of pages10
JournalChemistry and Biology
Volume13
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

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