Abstract 2160: Development of selective MELK kinase inhibitors for cancer treatments.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Maternal embryonic leucine zipper kinase (MELK) is an atypical member of the AMPK family of serine-threonine kinases that has been implicated in stem cell renewal, cell cycle progression, cytokinesis, mRNA splicing and apoptosis. MELK activity is correlated with its phosphorylation level, is cell cycle dependent and maximal during mitosis although direct upstream regulators of MELK kinase activity are unknown. This kinase is highly expressed in several types of solid cancers: colon, breast, ovary, lung, and brain and shows relatively low expression levels in normal tissues. MELK overexpression in patient-derived tumors strongly correlates with poor prognosis in glioblastoma and breast cancer. Moreover, siRNA mediated knockdown of MELK kinase significantly inhibits growth of tumor cell lines both in vitro and in vivo. Therefore, MELK kinase is an emerging and interesting target of significant potential for therapeutic intervention in cancer. In this study, we are reporting results for a series of new MELK kinase inhibitors that were developed at Selvita. Newly synthesized derivatives exert good selectivity and potency in MELK inhibitions with the low sub-micromolar range. Anticancer effects of these compounds were investigated in several cancer cell lines of solid tumor origin where the compounds were shown to induce cell death with low micromolar ED50 values. Compounds were also analyzed for their effects on cell death, proliferation, apoptosis, cell cycle parameters and ADME properties. Taken altogether, the presented data supports our rationale of using inhibitors of MELK kinases as a novel approach for the cancer therapy, especially for the treatment of glioblastoma and breast cancer. Citation Format: Piotr Kowalczyk, Paulina Wegrzyn, Przemyslaw Zawadzki, Edyta Palacz, Ewa Trebacz, Katarzyna Wiklik, Mariusz Milik, Adrian Zarebski, Karolina Krawczynska, Krzysztof Brzozka. Development of selective MELK kinase inhibitors for cancer treatments. [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 2160. doi:10.1158/1538-7445.AM2013-2160