An orally bioavailable 4-phenoxy-quinoline compound as a potent AURKB relocation blocker for cancer treatment

Abstract

We 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-substituted LXY18 was found to be a potent and orally bioavailable disruptor of cell division, at sub-nanomolar concentrations. LXY18 prevents cytokinesis by blocking AURKB relocalization in mitosis and exhibits broad-spectrum antimitotic activity in 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 of LXY18 may eliminate some drawbacks of direct catalytic inhibition of AURKs. Successful development of LXY18 as a clinical candidate for cancer treatment could enable a new, less toxic means of antimitotic attack that avoids drug resistance mechanisms.

Pharmacokinetics, Tissue Distribution, and Formulation Study of a Small-molecule Inhibitor of MKLP2, LG157

“…This study was carried out in compliance with the ARRIVE guidelines. 16 Rapid PK Assay. For PK and tissue distribution analysis, unless otherwise described, the animals were starved for 16 h before drug administration, with food being allowed 2 h post-treatment.…”