ABSTRACT
The screening of a small focused library of rhodanine derivatives as inhibitors of Bcl-2 proteins led to the discovery of two structurally related compounds with different binding profiles against the Bcl-XL and the Mcl-1 proteins. Subsequent NMR studies with mutant proteins and in silico docking studies provide a possible rationale for the observed specificity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclin D1/metabolism , Thiazolidines/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cyclin D1/antagonists & inhibitors , Cyclin D1/genetics , Fluorescence Polarization , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Models, Molecular , Mutagenesis, Site-Directed , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Thiazolidines/chemistry , Thiazolidines/pharmacologyABSTRACT
Despite their structural similarities, the natural products chelerythrine ( 5) and sanguinarine ( 6) target different binding sites on the pro-survival Bcl-X L protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-X L and the tagged Bak-BH3 peptide. The results led to structure-activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC 50 values.