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 IC₅₀ 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.
Highlights
Breast cancer is the most common malignancy among women worldwide[1]
We subsequently investigated in vivo anti-tumor effect of OTSSP167 by a xenograft model using MDAMB-231 cells (MELK-positive, triple-negative breast cancer cells)
The depletion of proteasome subunit alpha type 1 (PSMA1) or maternal embryonic leucine zipper kinase (MELK) expression in MDAMB-231 cells using siRNA significantly suppressed the formation of mammosphere (Fig 6F). These results suggest that OTSSP167 suppressed mammosphere formation of cancer stem cells through the reduction of phosphorylated PSMA1 by inhibition of the MELK activity
Summary
Breast cancer is the most common malignancy among women worldwide[1]. Treatments acting on molecular targets such as estrogen receptor or HER-2 for breast cancer have successfully improved the mortality rate, but a subset of the patients can still have little benefit with these therapies[3, 4]. Triple-negative breast cancer (TNBC), one of the breast cancer subtypes, develops more frequently in younger women and is known to be more aggressive with poor prognosis[5]. Since TNBC does not expresses either of HER-2, estrogen receptor, or progesterone receptor[6], no effective targeted therapy is presently available[5, 7]. The development of novel targeted drugs for such patients is urgently awaited
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