Proteomimetic libraries: design, synthesis, and evaluation of p53-MDM2 interaction inhibitors.
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.
Lu
Felice
F
Chemistry and Chemical Biology Graduate Program and Department of Pharmaceutical Chemistry, University of California, San Francisco, USA.
Chi
Seung-Wook
SW
Kim
Do-Hyoung
DH
Han
Kyou-Hoon
KH
Kuntz
Irwin D
ID
Guy
R Kiplin
RK