Nutlin‐3a‐aa: Improving the Bioactivity of a p53/MDM2 Interaction Inhibitor by Introducing a Solvent‐Exposed Methylene Group

Look away. Modification of the p53/MDM2 inhibitor Nutlin-3a with an exocyclic methylene group generated the more potent inhibitor Nutlin-3a-aa. X-ray analysis of MDM2-bound Nutlin-3a-aa indicated that the exocyclic methylene group of Nutlin-3a-aa faces away from the protein surface. Our data suggest the introduction of exocyclic methylene groups as a possible approach by which to optimize the conformation of bioactive molecules.

Abstract

Nutlin-3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized the derivative Nutlin-3a-aa bearing an additional exocyclic methylene group in the piperazinone moiety. Nutlin-3a-aa is more active than Nutlin-3a against purified wild-type MDM2, and is more effective at increasing p53 levels and releasing transcription of p53 target genes from MDM2-induced repression. X-ray analysis of wild-type MDM2-bound Nutlin-3a-aa indicated that the orientation of its modified piperazinone ring was altered in comparison to the piperazinone ring of MDM2-bound Nutlin-3a, with the exocyclic methylene group of Nutlin-3a-aa pointing away from the protein surface. Our data point to the introduction of exocyclic methylene groups as a useful approach by which to tailor the conformation of bioactive molecules for improved biological activity.

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