Orally Bioavailable 4-Phenoxy-quinoline Compound as a Potent Aurora Kinase B Relocation Blocker for Cancer Treatment

We investigated a novel 4-phenoxy-quinoline-based scaffoldthatmislocalizes the essential mitotic kinase, Aurora kinase B (AURKB).Here, we evaluated the impact of halogen substitutions (F, Cl, Br,and I) on this scaffold with respect to various drug parameters. Br-substituted LXY18 was found to be a potent and orally bioavailable disruptorof cell division, at sub-nanomolar concentrations. LXY18 prevents cytokinesis by blocking AURKB relocalization in mitosisand exhibits broad-spectrum antimitotic activity in vitro. With afavorable pharmacokinetic profile, it shows widespread tissue distributionincluding the blood-brain barrier penetrance and effectiveaccumulation in tumor tissues. More importantly, it markedly suppressestumor growth. The novel mode of action of LXY18 may eliminatesome drawbacks of direct catalytic inhibition of Aurora kinases. Successfuldevelopment of LXY18 as a clinical candidate for cancertreatment could enable a new, less toxic means of antimitotic attackthat avoids drug resistance mechanisms.