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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 ?M, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity.

SUBMITTER: Boltjes A

PROVIDER: S-EPMC4130243 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor.

Boltjes André A Huang Yijun Y van de Velde Rob R Rijkee Laurie L Wolf Siglinde S Gaugler James J Lesniak Katarzyna K Guzik Katarzyna K Holak Tad A TA Dömling Alexander A

ACS combinatorial science 20140711 8

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. Th ...[more]

PMID: 24983416

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