Integrating a phenotypic screening with a structural simplification strategy to identify 4-phenoxy-quinoline derivatives to potently disrupt the mitotic localization of Aurora kinase B.

Bioorganic & medicinal chemistry 2023 Feb 15

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We combined a mechanism-informed phenotypic screening (MIPS) assay with a structural simplification strategy to guide the discovery of compounds that disrupt the localization of the mitotic regulator, Aurora kinase B (AURKB), rather than inhibiting its catalytic activity. An initial hit 4-(4-methylthiophen-2-yl)-N-(4-(quinolin-4-yloxy)phenyl)phthalazin-1-amine was identified after screening an in-house library of small molecules and phenocopied the loss of function mutations in AURKB without inhibiting its catalytic activity. We isolated this hit compound activity to its 4-phenoxy-quinoline moiety. The fragment was further optimized into a class of new chemical entities that potently disrupt the mitotic localization of AURKB at low nanomolar concentrations and consequently elicit severe growth inhibition in diverse human cancer cell lines. A lead compound, N-(3-methoxy-5-(6-methoxyquinolin-4-yl)oxy)phenyl)acetamide possessed desirable pharmacokinetic properties such as AUC0-∞: 227.15 [ng∙h/mL/(mg/kg)]; Cmax: 3378.52 ng/mL T1/2: 3.52 h; and F%: 42 % and produced the AURKB-inhibitory phenotypes in a mouse xenograft model. A lead compound is a powerful tool for interrogating the regulation of AURKB and has the potential to be further developed as a first-in-class oncology therapeutic. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Gang Lv, Qiong Shi, Ting Zhang, Jinhua Li, Yan Long, Wenhui Zhang, Namrta Choudhry, Kevin Yang, Hongmei Li, Julia Kalashova, Chenglu Yang, Xiaohu Zhou, Mallu Chenna Reddy, Kishore Kumar Anantoju, Shenqiu Zhang, Jing Zhang, Thaddeus D Allen, Hong Liu, Naganna Nimishetti, Dun Yang. Integrating a phenotypic screening with a structural simplification strategy to identify 4-phenoxy-quinoline derivatives to potently disrupt the mitotic localization of Aurora kinase B. Bioorganic & medicinal chemistry. 2023 Feb 15;80:117173