Abstract LB-300: Development of an orally-administrative MELK (maternal embryonic leucine zipper kinase)-targeting small molecule inhibitor that suppresses the growth of various types of human cancer.

Abstract

Abstract Breast cancer is the most common malignancy among women worldwide. Treatment for breast cancer acting on molecular targets in critical signaling pathways in cancer cells have successfully reduced the motility rate in a subset of breast cancer patients, but a significant portion of patients expect to have little benefit from these treatments. Therefore, development of new therapeutics for those patients is urgently required. We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was highly upregulated in multiple types of human cancer including breast, prostate and lung cancers, and plays indispensable roles in cancer cell survival, particularly in the maintenance of tumor-initiating cells. Although several substrates of MELK were reported, we still do not understood fully how MELK contributes to breast cancer development and/or progression. To elucidate the MELK signaling pathway in breast cancer cells, we screened and identified two novel MELK substrates, DBNL and PSMA1, which were also found to play critical roles in human carcinogenesis and mammary tumor-initiating cells. Furthermore, 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 IC50 of 0.41 nM. OTSSP167 inhibited the phosphorylation of these two substrates by MELK as well as 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. Here, we report the biological function of novel substrates of MELK and the first MELK inhibitor OTSSP167 that is a promising compound to treat various types of human cancer. Citation Format: Suyoun Chung, Hanae Suzuki, Takashi Miyamoto, Naofumi Takamatsu, Ayako Tatsuguchi, Koji Ueda, Kyoko Kijima, Yo Matsuo, Yusuke Nakamura. Development of an orally-administrative MELK (maternal embryonic leucine zipper kinase)-targeting small molecule inhibitor that suppresses the growth of various types of human cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-300. doi:10.1158/1538-7445.AM2013-LB-300