Abstract C26: Development of selective MELK kinase inhibitors for breast cancer treatment
Authors: Kowalczyk Piotr , Węgrzyn Paulina , Prokopowicz Monika , Knop Martyna , Mazur Karolina , Dziedzic Katarzyna , Gluza Karolina , Knop Martyna , Dziedzic Katarzyna , Mazur Karolina , Radzimierski Adam , Commandeur Claude , Zawadzka Magdalena , Bloudoff Kristjan , Vaillancourt Fred , Larsen Nick , Wang John , Reynolds Dom , Ito Daisuke , Zou Jian , Aicher Michelle , Smith Pete , Zhu Ping , Brzózka Krzysztof 
Published: May 2016

Abstract
Breast cancer is the second most common cancer in the world and the most frequent cancer among women. Despite the progress in developing breast cancer therapies, approximately, 15% of all breast cancers are diagnosed as triple negative breast cancer (TNBC) and due to the lack of estrogen and progesterone receptors this subgroup of patients remains difficult to treat with hormonal therapies. Additionally, therapies targeting HER2, such as Herceptin, are also inefficient against TNBC. In recent years, maternal embryonic leucine zipper kinase (MELK) has been identified as a novel oncogenic target that is highly expressed in several types of solid cancers: breast (especially triple negative breast cancer), colon, ovary, lung, and brain and present at low levels in normal tissues. MELK overexpression in patient tumors strongly correlates with poor prognosis in glioblastoma and breast cancer. siRNA mediated knockdown of MELK kinase significantly inhibits growth of tumor cell lines both in vitro and in vivo. Therefore, MELK kinase is emerging as a novel and interesting target with significant potential for therapeutic intervention in cancer.
MELK is an atypical member of the AMPK family of serine-threonine kinases that been implicated has been implicated in stem cell renewal, cell cycle progression, cytokinesis, mRNA splicing and apoptosis. Its 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. Despite the fact that the exact function is currently under investigation, selective targeting of MELK may be an effective cancer treatment strategy in a wide range of solid tumors. In this study, we are reporting development of a series of selective MELK kinase inhibitors. Synthesized compounds exert excellent selectivity and potency in MELK inhibition in a low nanomolar range. Therapeutic effect of the compounds was investigated in the panel of breast cancer cell lines with different genetic background as well as with different MELK kinase levels; it was shown that for some cell lines compounds induced cell death with nanomolar ED50 values. The compound's effect on the proliferation and in the colony formation assay was also investigated. Taken altogether, the presented data supports our rationale of using MELK kinase inhibitors as a novel approach for the cancer therapy.
Citation Format: Piotr Kowalczyk, Paulina Węgrzyn, Monika Prokopowicz, Martyna Knop, Karolina Mazur, Katarzyna Dziedzic, Karolina Gluza, Martyna Knop, Katarzyna Dziedzic, Karolina Mazur, Adam Radzimierski, Claude Commandeur, Magdalena Zawadzka, Kristjan Bloudoff, Fred Vaillancourt, Nick Larsen, John Wang, Dom Reynolds, Daisuke Ito, Jian Zou, Michelle Aicher, Pete Smith, Ping Zhu, Krzysztof Brzózka. Development of selective MELK kinase inhibitors for breast cancer treatment. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C26.