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.

journal_name

Oncogene

journal_title

Oncogene

authors

Berezov A,Cai Z,Freudenberg JA,Zhang H,Cheng X,Thompson T,Murali R,Greene MI,Wang Q

doi

10.1038/onc.2011.377

subject

Has Abstract

pub_date

2012-04-12 00:00:00

pages

1938-48

issue

15

eissn

0950-9232

issn

1476-5594

pii

onc2011377

journal_volume

31

pub_type

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