Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer

// Suyoun Chung 1 , Hanae Suzuki 2 , Takashi Miyamoto 2 , Naofumi Takamatsu 2 , Ayako Tatsuguchi 3 , Koji Ueda 3 , Kyoko Kijima 2 , Yusuke Nakamura 1,4 and Yo Matsuo 2 1 Department of Medicine and Surgery, The University of Chicago, Chicago, IL, USA 2 OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan 3 Laboratory for Biomarker Development, RIKEN, Yokohama, Japan 4 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan Correspondence: Yusuke Nakamura, email: // Yo Matsuo, email: // Keywords : oncogene, drug discovery, kinase inhibitor, cancer stem cell Received : December 05, 2012, Accepted : December 20, 2012, Published : December 21, 2012 Abstract We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was also reported to be highly upregulated in multiple types of human cancer. It was implied to play indispensable roles in cancer cell survival and indicated its involvement in the maintenance of tumor-initiating cells. We conducted a high-throughput screening of a compound library followed by structure-activity relationship studies, and successfully obtained a highly potent MELK inhibitor OTSSP167 with IC 50 of 0.41 nM. OTSSP167 inhibited the phosphorylation of PSMA1 (proteasome subunit alpha type 1) and DBNL (drebrin-like), which we identified as novel MELK substrates and are important for stem-cell characteristics and invasiveness. The compound suppressed mammosphere formation of breast cancer cells and exhibited significant tumor growth suppression in xenograft studies using breast, lung, prostate, and pancreas cancer cell lines in mice by both intravenous and oral administration. This MELK inhibitor should be a promising compound possibly to suppress the growth of tumor-initiating cells and be applied for treatment of a wide range of human cancer.