Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905)

…, J Alley, J Anthony, C Barrett, I Bharathan…

文献索引：Duffey, Matthew O.; Vos, Tricia J.; Adams, Ruth; Alley, Jennifer; Anthony, Justin; Barrett, Cynthia; Bharathan, Indu; Bowman, Douglas; Bump, Nancy J.; Chau, Ryan; Cullis, Courtney; Driscoll, Denise L.; Elder, Amy; Forsyth, Nancy; Frazer, Jonathan; Guo, Jianping; Guo, Luyi; Hyer, Marc L.; Janowick, David; Kulkarni, Bheemashankar; Lai, Su-Jen; Lasky, Kerri; Li, Gang; Li, Jing; Liao, Debra; Little, Jeremy; Peng, Bo; Qian, Mark G.; Reynolds, Dominic J.; Rezaei, Mansoureh; Scott, Margaret Porter; Sells, Todd B.; Shinde, Vaishali; Shi, Qiuju Judy; Sintchak, Michael D.; Soucy, Francois; Sprott, Kevin T.; Stroud, Stephen G.; Nestor, Michelle; Visiers, Irache; Weatherhead, Gabriel; Ye, Yingchun; Damore, Natalie Journal of Medicinal Chemistry, 2012 , vol. 55, # 1 p. 197 - 208

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被引用次数: 20

摘要

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic–pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth ...