Discovery of a novel small molecule binding site of human survivin.
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.
Wendt
Michael D
MD
Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA. mike.d.wendt@abbott.com
Sun
Chaohong
C
Kunzer
Aaron
A
Sauer
Daryl
D
Sarris
Kathy
K
Hoff
Ethan
E
Yu
Liping
L
Nettesheim
David G
DG
Chen
Jun
J
Jin
Sha
S
Comess
Kenneth M
KM
Fan
Yihong
Y
Anderson
Steven N
SN
Isaac
Binumol
B
Olejniczak
Edward T
ET
Hajduk
Philip J
PJ
Rosenberg
Saul H
SH
Elmore
Steven W
SW
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D019281:Dimerization; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008869:Microtubule-Associated Proteins / Q000737:chemistry*; D015335:Molecular Probes / Q000737:chemistry*; D009363:Neoplasm Proteins / Q000737:chemistry*; D011487:Protein Conformation; D000077022:Survivin
C107489:BIRC5 protein, human; D015853:Cysteine Proteinase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008869:Microtubule-Associated Proteins; D015335:Molecular Probes; D009363:Neoplasm Proteins; D000077022:Survivin