Polo-box PLK1 Inhibitors Target Tumors Resistant to ATP Competitive Compounds

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Polo-like kinase 1 (PLK1) is a central player in regulating entry into and progression through mitosis. Many studies have validated PLK1 as an anti-tumor drug target, and its inhibition is potently anti-proliferative to cancer cells. However, recent data suggests that there are two major disadvantages of the conventional approach to blocking the kinase activity of PLK1. First, both general kinome and PLK family specificity is an issue with ATP competitive compounds as they commonly inhibit all paralogs in the Polo-kinase family (including PLK3, a known tumor suppressor). Second, a recent study indicates that a single point mutant in the active site of PLK1 (Cys67Val) results in complete resistance to structurally distinct ATP competitive inhibitors currently in clinical trials, suggesting that the emergence of resistance in the clinic against these agents is a near certainty. Therefore a strategy different from targeting the catalytic domains is urgently needed. PPI Pharmaceuticals will develop PLK1 selective non- ATP competitive inhibitors as effective anti-tumor therapeutics that retain activity against active site mutants resistant to conventional kinase inhibitors. Such compounds will have significant potential for development as anti-tumor agents with decreased likelihood of tumor resistance and off-target effects.