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ACS Comb Sci. 2014 Aug 11;16(8):393-6. doi: 10.1021/co500026b. Epub 2014 Jul 11.

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

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Drug Design, University of Groningen , A. Deusinglaan 1, 9713 AV Groningen, Netherlands.


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.

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