Qi, JingDong, ZizhengLiu, JianguoPeery, Robert C.Zhang, ShaoboLiu, JingyuanZhang, Jian-Ting2016-10-202016-10-202016-01Qi, J., Dong, Z., Liu, J., Peery, R. C., Zhang, S., Liu, J.-Y., & Zhang, J.-T. (2016). Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors. Cancer Research, 76(2), 453–462. http://doi.org/10.1158/0008-5472.CAN-15-1874https://hdl.handle.net/1805/11212Many 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.enPublisher Policydrug discoveryprotein-protein interactionsurvivinArticle