Discovery of a novel small molecule binding site of human survivin |
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Authors: | Wendt Michael D Sun Chaohong Kunzer Aaron Sauer Daryl Sarris Kathy Hoff Ethan Yu Liping Nettesheim David G Chen Jun Jin Sha Comess Kenneth M Fan Yihong Anderson Steven N Isaac Binumol Olejniczak Edward T Hajduk Philip J Rosenberg Saul H Elmore Steven W |
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Affiliation: | Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA. mike.d.wendt@abbott.com |
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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. |
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