Disabling the mitotic spindle and tumor growth by targeting a cavity-induced allosteric site of survivin

Abstract

Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis. Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy. Epidermal growth factor receptor and Her/neu-transformed human tumors in particular exhibit high levels of survivin. The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein. We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces. S12, a lead compound identified in the screen, can bind to the survivin protein at the intended target site. Moreover, S12 alters spindle formation, causing mitotic arrest and cell death, and inhibits tumor growth in vitro and in vivo. Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity. Thus, the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers.

Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function

“…37 Targeting a cavity-induced allosteric site of Survivin led to disturbed alignment of the chromosomes on the metaphase plate resulting in apoptosis, without affecting overall DNA synthesis. 38 However, in our model, we did not observe increased apoptosis but increased DNA content in individual hepatocyte nuclei. In summary, these studies could provide a possible explanation for reduced mitotic activity in combination with increased polyploidy of Alb-surv À / À hepatocytes in our regeneration experiments.…”

Non-motor Spindle Proteins as Cancer Chemotherapy Targets

“…However, drug screens may not always require activity readouts, but can be based on molecular analysis of the protein structure. Rational drug design based on protein structure is an alternative, as exemplifi ed by S12, a drug that interferes with a specifi c Survivin motif [ 193 ], which was developed using an in-house allosteric modeling drug discovery (CIAM) algorithm.…”

“…YM155, a drug that interferes with induction of the Survivin promoter, has entered clinical trials, with inconclusive results thus far in non-small-cell lung cancer [ 192 ]. Another drug, S12, that allosterically blocks Survivin interactions with CPC binding partners, shows promise as an inhibitor of tumor growth in vivo [ 193 ]. Although Survivin has been targeted because of a presumptive anti-apoptotic function, it appears that its principal function in cells is as a passenger protein in mitosis [ 194 ], and it is thus appropriate to discuss Survivin solely as a mitotic chemotherapy target.…”

Sequestering survivin to functionalized nanoparticles: a strategy to enhance apoptosis in cancer cells

“…Immunotherapy is a relatively new strategy compared to the other methods, and investigations are being carried out to find the epitopes that generate the strongest immunodominant, immunoprevalent T-cell reaction against survivin 39 . Finally, the use of small molecule ligand that simply binds to the protein and disrupts survivin’s activity may present a more focused and less destructive therapeutic approach if the binding can be designed to only occur in a tumor of interest 30,40 . Unfortunately, the widespread development of new binding ligands for survivin is frustrated by the perceived lack of structural pockets of the appropriate geometry and hydrophilicity on the protein that act as a druggable site 33 .…”