title: Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors.
abstract: Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule-based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable.
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Zizheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Peery
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Computer and Information Science, Indiana University-Purdue University at Indianapolis, Indiana. jianzhan@iu.edu jliu2@iu.edu.
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana. IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana. jianzhan@iu.edu jliu2@iu.edu.
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D019281:Dimerization; D004195:Disease Models, Animal; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin