Maternal embryonic leucine zipper kinase (MELK) is highly expressed in various types of intractable malignancies, including glioblastoma multiforme (GBM) and breast cancer, in particular triple negative breast cancer (TNBC), where level of overexpression correlates with poor prognosis and aggressive disease course. Although there are some ATP-competitive MELK inhibitors in literature, no inhibitor addressed the challenge of specificity with respect to off-target enzymes closely related to MELK and there are no FDA-approved drugs of MELK at present. Our discovery approach for finding a novel MELK inhibitor through kinase inhibitor library screening, structure-guided design of a series of novel indolinone derivatives with subnanomolar inhibition will be presented. We identified various micro molar inhibitors that have scaffolds including imidazopyridine, indazole, pyrazole and indolinone through screening; then synthesized a library of novel indolinone derivatives by structure-guided design and discovered three tight binding inhibitors with Ki &lt; 1 nM (Graphical Abstract). The most potent compound (MELK-In-17) decreases proliferation of TNBC cells expressing high levels of MELK.

Discovery of novel indolinone derivatives as potent MELK inhibitors

253rd National Meeting (2017)

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