title: Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction.
abstract: The transcription factor p53 is the main tumour suppressor in cells and many cancer types have p53 mutations resulting in a loss of its function. In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2) via a direct protein-protein interaction. We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. The first set was designed to directly mimic the α-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural α-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an α-helix template. The key step of the synthesis involved the cyclisation of substituted dipeptides. The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis. This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Gothenburg, Sweden.
authors.forename: Mariell
authors.initials: M
authors.lastname: Pettersson
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Gothenburg, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Quant
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee, 38105, United States of America.
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee, 38105, United States of America.
authors.forename: Luigi
authors.initials: L
authors.lastname: Iconaru
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee, 38105, United States of America.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Kriwacki
authors.affiliation: Molecular Interaction Analysis Shared Resource, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee, 38105, United States of America.
authors.forename: M Brett
authors.initials: MB
authors.lastname: Waddell
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee, 38105, United States of America.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Gothenburg, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Luthman
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Gothenburg, Sweden.
authors.forename: Morten
authors.initials: M
authors.lastname: Grøtli
mesh_terms: D001665:Binding Sites; D060326:Chemistry Techniques, Synthetic; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D054659:Diketopiperazines; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2