Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine kinase and an atypical member of the SNF1/AMPK family. MELK has been identified as part of a gene signature representing undifferentiated cancers, which are thought to be more aggressive in behavior and linked to poor patient outcome. MELK has been proposed as a potential therapeutic target based on its overexpression in a broad spectrum of cancer types, including breast, ovarian, lung, pancreas, and colorectal. An increase in MELK expression correlates with more aggressive forms of astrocytoma, breast cancer, melanoma, and glioblastoma. Among breast cancer subtypes, MELK is more highly expressed in triple-negative (estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and no HER2 overexpression) than in ER-positive. A key issue remains our poor understanding of the molecular mechanism underpinning the role of MELK in cancer due to the lack of selective pharmacological agents that inhibit its activity. In this poster, we will discuss the successful use of virtual screening hit finding strategy to uncover selective MELK hits with good physical chemical properties. The optimization of these hits into highly potent, selective, cell permeable MELK inhibitors and their use to understand MELK biology will be presented. Finally, our strategies to overcome PK challenges and enable in vivo dosing will also be discussed

MELK as a valid cancer therapeutic target? From virtual screening to highly selective in vivo tool compounds

253rd National Meeting (2017)

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