title: Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor.
abstract: On the basis of our recently resolved first cocrystal structure of Mdm4 in complex with a small molecule inhibitor (PDB ID 3LBJ ), we devised an approach for the generation of potential Mdm4 selective ligands. We performed the Ugi four-component reaction (Ugi-4CR) in 96-well plates with an indole fragment, which is specially designed to mimic Trp23, a key amino acid for the interaction between p53 and Mdm4. Generally the reaction yielded mostly precipitates collected by 96-well filter plates. The best hit compound was found to be active and selective for Mdm4 (Ki=5 μM, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity.
authors.affiliation: Drug Design, University of Groningen , A. Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors.forename: André
authors.initials: A
authors.lastname: Boltjes
authors.forename: Yijun
authors.initials: Y
authors.lastname: Huang
authors.forename: Rob
authors.initials: R
authors.lastname: van de Velde
authors.forename: Laurie
authors.initials: L
authors.lastname: Rijkee
authors.forename: Siglinde
authors.initials: S
authors.lastname: Wolf
authors.forename: James
authors.initials: J
authors.lastname: Gaugler
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Lesniak
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Guzik
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
mesh_terms: D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D060066:Protein Interaction Maps / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D008024:Ligands; D057786:Peptidomimetics; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2