title: Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors.
abstract: The CREB binding protein (CBP) is a human transcriptional coactivator consisting of several conserved functional modules, which interacts with distinct transcription factors including nuclear receptors, CREB, and STAT proteins. Despite the importance of CBP in transcriptional regulation, many questions regarding the role of its particular domains in CBP functions remain unanswered. Therefore, developing small molecules capable of selectively modulating a single domain of CBP is of invaluable aid at unraveling its prominent activities. Here we report the design, synthesis, and biological evaluation of conformationally restricted peptides as novel modulators for the acetyl-lysine binding bromodomain (BRD) of CBP. Utilizing a target structure-guided and computer-aided rational design approach, we developed a series of cyclic peptides with affinity for CBP BRD significantly greater than those of its biological ligands, including lysine-acetylated histones and tumor suppressor p53. The best cyclopeptide of the series exhibited a K(d) of 8.0 μM, representing a 24-fold improvement in affinity over that of the linear lysine 382-acetylated p53 peptide. This lead peptide is highly selective for CBP BRD over BRDs from other transcriptional proteins. Cell-based functional assays carried out in colorectal carcinoma HCT116 cells further demonstrated the efficacy of this compound to modulate p53 stability and function in response to DNA damage. Our results strongly argue that these CBP modulators can effectively inhibit p53 transcriptional activity by blocking p53K382ac binding to CBP BRD and promoting p53 instability by changes of its post-translational modification states, a different mechanism than that of the p53 inhibitors reported to date.
authors.affiliation: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1677, New York, New York 10029, United States.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gerona-Navarro
authors.lastname: Yoel-Rodríguez
authors.forename: Shiraz
authors.initials: S
authors.lastname: Mujtaba
authors.forename: Antonio
authors.initials: A
authors.lastname: Frasca
authors.forename: Jigneshkumar
authors.initials: J
authors.lastname: Patel
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: Roman
authors.initials: R
authors.lastname: Osman
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
mesh_terms: D050882:CREB-Binding Protein / Q000187:drug effects*; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D010456:Peptides, Cyclic; D016159:Tumor Suppressor Protein p53; D050882:CREB-Binding Protein