Orally Bioavailable 4-Phenoxy-quinoline Compound as a Potent Aurora Kinase B Relocation Blocker for Cancer Treatment
Year: 2023
Type: article
Abstract: 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 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 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 LXY18 may eliminate some drawbacks of direct catalytic inhibition of Aurora kinases. 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.
Authors: 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
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4385066588