Inhibitor of CBP Histone Acetyltransferase Downregulates p53 Activation and Facilitates Methylation at Lysine 27 on Histone H3 Abstract: Tumor suppressor p53-directed apoptosis triggers the loss of normal cells, which contributes to the side-effects of anticancer therapies. Thus, small molecules with potential to downregulate the activation of p53 could minimize pathology form anticancer therapies. Acetylation of p53 mediated by the histone acetyltransferase (HAT) domain is the hallmark of coactivator CREB-binding protein (CBP) epigenetic function. During genotoxic stress, CBP HAT-mediated acetylation is essential for the activation of p53 to transcriptionally govern target genes, which control cellular responses. Here, we present a small molecule, NiCur, which blocks CBP HAT activity as well as downregulates p53 activation upon genotoxic stress. Computational modeling reveals that NiCur docks into the active site of CBP HAT. On CDKN1A promoter, NiCur diminishes the recruitment of p53 and RNA Pol II as well as the levels of acetylation on histone H3. Specifically, NiCur reduces the levels of acetylation at lysine 27 on histone H3, which concomitantly increases the levels of methylation at lysine 27. Finally, NiCur attenuates p53-directed apoptosis by inhibiting the caspase 3 activity and cleavage of PARP in normal gastrointestinal epithelial cells. Collectively, NiCur demonstrates the potential to reprogram the chromatin landscape and modulate biological outcomes of CBP-mediated acetylation under normal and disease conditions.