Abstract
AbstractWe investigated a novel 4-phenoxy-quinoline-based scaffold that mislocalizes the essential mitotic kinase, AURKB. Here, we evaluated the impact of halogen substitutions (F, Cl, Br, I) on this scaffold with respect to various drug parameters. Br-substitutedLXY18was found to be a potent and orally bioavailable disruptor of cell division, at sub-nanomolar concentrations.LXY18prevents cytokinesis by blocking AURKB relocalization in mitosis and exhibits broad-spectrum antimitotic activityin vitro. With a favorable PK profile, it shows widespread tissue distribution including the blood-brain barrier penetrance and effective accumulation in tumor tissues. More importantly, it markedly suppresses tumor growth. The novel mode of action ofLXY18may eliminate some drawbacks of direct catalytic inhibition of AURKs. Successful development ofLXY18as a clinical candidate for cancer treatment could enable a new, less toxic means of antimitotic attack that avoids drug resistance mechanisms.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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