Kinases remain a popular therapeutic target for anti-cancer drug development. Nek2 is a Ser/Thr kinase that is overabundant in several highly invasive cancers, such as triple-negative breast, cervical, and ovarian cancers. Dysregulated Nek2 activity due to overexpression has been associated with cancer metastasis and drug resistance. Unfortunately, no Nek2 inhibitory agent has advanced to clinical trial thus far.  Thus, non-toxic small molecule inhibitors exhibiting potent anti-cancer activities are urgently needed. In our laboratory, we have developed Nek2 kinase overexpression model in <i>Drosophila melanogaster</i> and showed that the overabundance of Nek2 kinase can upregulate migratory and proliferative pathways via activation of Akt/PI3K signaling. Using this model and a bioinformatics-based approach, we identified a novel, non-toxic, drug-like quinoline-based pharmacophore for Nek2 kinase from a library of EGFR drug candidates. Since the expression of both Nek2 and EGFR kinases is high in many highly aggressive tumors, we hypothesize that dual inhibition of both Nek2 and EGFR kinases by a single agent should render desirable anti-cancer activities.  Herein, we report the development of a quinoline-derived compound library that inhibits both Nek2 and EGFR kinases potently. The lead inhibitory compound also exhibits desirable cytotoxicity in several human cancer cell lines. We anticipate that this class of dual-action inhibitory agents will impart a superior therapeutic index in cancers where Nek2 and EGFR expressions are abnormally high.

Quinoline-based dual-action inhibitors of Nek2 kinase with cellular activity

ACS Spring 2022

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