Polo box PLK Inhibitors Target Tumors Resistant to ATP Competitive Compounds

Polo like kinase PLK is a central player in regulating entry into and progression through mitosis Many studies have validated PLK 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 PLK 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 PLK a known tumor suppressor Second a recent study indicates that a single point mutant in the active site of PLK Cys Val 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 PLK 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 PPI Pharmaceuticals will develop PLK selective non ATP competitive inhibitors as effective anti tumor therapeutics through the use of the REPLACE strategy These compounds will 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