Discovery of potent maternal embryonic leucine zipper kinase (MELK) inhibitors of novel chemotypes using structure-based pharmacophores

Maternal embryonic leucine zipper kinase (MELK) is a serine-threonine kinase. Several studies have revealed its role as a regulator in the tumorigenesis of various cancers. Consequently, MELK has been considered as an attractive therapeutic target for cancer management. Herein, we report pharmacophore models extracted from crystallographic complexes of potent ligands bound to MELK protein. The resulting models were evaluated by Receiver Operating Characteristic (ROC) analysis, and the best models were employed as search queries to screen the national cancer institute for potent inhibitors. The anti-MELK bioactivities of acquired hits were evaluated in vitro. Moreover, best anti-MELK hits were further evaluated against lung and cervical cancer cells (A549 and HeLa, respectively) using cell viability MTT assay. The enzymatic assay identified six potent hits with IC50 values ranging from nanomolar to low micromolar values. The most active hit showed anti-MELK IC50 of 134.6 nM. Likewise, these hits significantly inhibited the growth of tested cancer cell lines. Interestingly, four of the identified inhibitors have chemical scaffolds that are notably different from those of reported MELK inhibitors. This study highlights the use of X-ray crystallographic structures to boost the drug discovery process.