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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Survivin, an inhibitor of apoptosis protein, is crucial for mitosis and overexpressed in various human cancers, particularly EGFR and Her/neu-transformed tumors.
• Survivin's dimerization through a conserved region is vital for its subcellular localization and function, making it an attractive therapeutic target.

Purpose of the Study:

• To identify small molecules targeting a specific cavity adjacent to survivin dimerization surfaces.
• To validate a novel therapeutic target site in survivin and develop a new class of anti-cancer small molecules.

Main Methods:

• High-throughput screening to identify small molecules binding to survivin.
• Biochemical assays to confirm binding of lead compound S12 to the target site.
• In vitro and in vivo studies to evaluate S12's effect on cancer cell mitosis, tumor growth, and toxicity.

Main Results:

• Identified small molecules targeting a cavity near survivin dimerization surfaces.
• Lead compound S12 binds to survivin at the intended site, alters spindle formation, and induces mitotic arrest.
• S12 causes cancer cell death in the premetaphase stage without general toxicity and inhibits tumor growth in vitro and in vivo.

Conclusions:

• A novel therapeutic target site adjacent to survivin dimerization surfaces has been validated.
• The small molecule S12 demonstrates efficacy in inhibiting cancer cell proliferation and tumor growth.
• This study presents a promising strategy for developing novel small molecule therapeutics for human cancers targeting survivin.