Proteomimetic libraries: Design, synthesis, and evaluation of p53-MDM2 interaction inhibitors

Felice Lu, Seung Wook Chi, Do Hyoung Kim, Kyou Hoon Han, Irwin D. Kuntz, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

The p53-MDM2 interaction regulates p53-mediated cellular responses to DNA damage, and MDM2 is overexpressed in 7% of all cancers. Structure-based computational design was applied to this system to design libraries centered on a scaffold that projects side chain functionalities with distance and angular relationships equivalent to those seen in the MDM2 interacting motif of p53. A library of 173 such compounds was synthesized using solution phase parallel chemistry. The in vitro competitive ability of the compounds to block p53 peptide binding to MDM2 was determined using a fluorescence polarization competition assay. The most active compound bound with Kd = 12 μM, and its binding was characterized by 15N-1H HSQC NMR.

Original languageEnglish
Pages (from-to)315-325
Number of pages11
JournalJournal of Combinatorial Chemistry
Volume8
Issue number3
DOIs
StatePublished - May 2006

ASJC Scopus subject areas

  • General Chemistry

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