Fragment-Based Library Generation for the Discovery of a Peptidomimetic p53-Mdm4 Inhibitor

• DOI: 10.1021/co500026b
• Publication Date: 2014-07-01T21:36:27Z
• Authors: André Boltjes; Yijun Huang; Rob van de Velde; Laurie Rijkee; Siglinde Wolf; James Gaugler; Katarzyna Lesniak; Katarzyna Guzik; Tad A. Holak; Alexander Dömling
• Keywords: library generation; LEAD COMPOUNDS; Models, Molecular; P53; 0303 health sciences; PROTEINS; Ugi four-component reaction; Proto-Oncogene Proteins c-mdm2; Ligands; peptidomimetic p53-Mdm4 inhibitor; Molecular Docking Simulation; 03 medical and health sciences; ANTAGONISTS; Drug Discovery; Humans; Peptidomimetics; Protein Interaction Maps; Tumor Suppressor Protein p53; MDMX

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.