Logo image
Back
Discovery of a novel small molecule binding site of human survivin
Journal article   Peer reviewed

Discovery of a novel small molecule binding site of human survivin

Michael D. Wendt, Chaohong Sun, Aaron Kunzer, Daryl Sauer, Kathy Sarris, Ethan Hoff, Liping Yu, David G. Nettesheim, Jun Chen, Sha Jin, …
Bioorganic & medicinal chemistry letters, Vol.17(11), pp.3122-3129
06/01/2007
DOI: 10.1016/j.bmcl.2007.03.042
PMID: 17391963
url
https://doi.org/10.7270/q2m04534View
Open Access

Abstract

Survivin is one of the most tumor-specific genes in the human genome and is an attractive target for cancer therapy. However, small-molecule ligands for survivin have not yet been described. Thus, an interrogation of survivin which could potentially both validate a small-molecule therapy approach, and determine the biochemical nature of any of survivin’s functions has not been possible. Here we describe the discovery and characterization of a small molecule binding site on the survivin surface distinct from the Smac peptide-binding site. The new site is located at the dimer interface and exhibits many of the features of highly druggable, biologically relevant protein binding sites. A variety of small hydrophobic compounds were found that bind with moderate affinity to this binding site, from which one lead was developed into a group of compounds with nanomolar affinity. Additionally, a subset of these compounds are adequately water-soluble and cell-permeable. Thus, the structural studies and small molecules described here provide tools that can be used to probe the biochemical role(s) of survivin, and may ultimately serve as a basis for the development of small molecule therapeutics acting via direct or allosteric disruption of binding events related to this poorly understood target.
 Ligand Survivin

Details

Metrics

8 Record Views
72 Times Cited - Web of Science
Logo image