Orally Bioavailable 4-Phenoxy-quinoline Compound as a Potent Aurora Kinase B Relocation Blocker for Cancer Treatment.
Jinhua Li, Ting Zhang, Qiong Shi, Gang Lv, Xiaohu Zhou, Namrta Choudhry, Julia Kalashova, Chenglu Yang, Hongmei Li, Yan Long, Balasubramaniyan Sakthivel, Naganna Nimishetti, Hong Liu, Thaddeus D Allen, Jing Zhang, Dun Yang
We investigated a novel 4-phenoxy-quinoline-based scaffold that mislocalizes 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 was found to be a potent and orally bioavailable disruptor of cell division, at sub-nanomolar concentrations. prevents cytokinesis by blocking AURKB relocalization in mitosis and exhibits broad-spectrum antimitotic activity in vitro. With a favorable pharmacokinetic 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 may eliminate some drawbacks of direct catalytic inhibition of Aurora kinases. Successful development of as a clinical candidate for cancer treatment could enable a new, less toxic means of antimitotic attack that avoids drug resistance mechanisms.
References
Front Cell Dev Biol. 2015 Mar 05;3:14
[PMID: 25798441]
