title: Proteomimetic libraries: design, synthesis, and evaluation of p53-MDM2 interaction inhibitors.
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 K(d) = 12 microM, and its binding was characterized by (15)N-(1)H HSQC NMR.
authors: Chemistry and Chemical Biology Graduate Program and Department of Pharmaceutical Chemistry, University of California, San Francisco, USA.
authors: Felice
authors: F
authors: Lu
authors: Seung-Wook
authors: SW
authors: Chi
authors: Do-Hyoung
authors: DH
authors: Kim
authors: Kyou-Hoon
authors: KH
authors: Han
authors: Irwin D
authors: ID
authors: Kuntz
authors: R Kiplin
authors: RK
authors: Guy