In the majority of cancers, the p53 pathway is non-functional because either p53 is mutated or the negative regulators of p53, MDM2 and MDM4, are over-expressed, preventing p53 from suppressing cancer cell growth. Using innovative computational approaches our lab set forth to predicted and validated novel classes of MDM2 and MDM4 inhibitors based on multicomponent reaction (MCR) chemistry.Computational screening of a very large chemical space of billions of potential small molecules inhibitors of p53/MDM2/MDM4 derived from MCRs containing tryptophan mimics were achieved using our web-based design ANCHOR.QUERY  (http://anchorquery.ccbb.pitt.edu/).  Complex drug like compounds were synthesized in one-pot MCR fashion. Compounds were tested via various in vitro and in vivo assays. Lead compounds based on different scaffolds were co-crystallized with MDM2 or MDM4. Herein we describe our ANCHOR-based approach for the discovery of two scaffolds, and give insight into the p53/MDM2/MDM4 chemotype requirements based on our multiple co-crystal structures.

Parallel discovery and co-crystallization of multiple small molecule scaffolds to inhibit P53/MDM2/MDM4 using <i>ANCHOR.QUERY</i>

244th National Meeting (2012)

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Parallel discovery and co-crystallization of multiple small molecule scaffolds to inhibit P53/MDM2/MDM4 using ANCHOR.QUERY