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Discovery of a Potent and Orally Bioavailable Benzolactam-Derived Inhibitor of Polo-Like Kinase 1 (MLN0905)

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journal contribution
posted on 22.02.2016, 08:50 by Matthew O. Duffey, Tricia J. Vos, Ruth Adams, Jennifer Alley, Justin Anthony, Cynthia Barrett, Indu Bharathan, Douglas Bowman, Nancy J. Bump, Ryan Chau, Courtney Cullis, Denise L. Driscoll, Amy Elder, Nancy Forsyth, Jonathan Frazer, Jianping Guo, Luyi Guo, Marc L. Hyer, David Janowick, Bheemashankar Kulkarni, Su-Jen Lai, Kerri Lasky, Gang Li, Jing Li, Debra Liao, Jeremy Little, Bo Peng, Mark G. Qian, Dominic J. Reynolds, Mansoureh Rezaei, Margaret Porter Scott, Todd B. Sells, Vaishali Shinde, Qiuju Judy Shi, Michael D. Sintchak, Francois Soucy, Kevin T. Sprott, Stephen G. Stroud, Michelle Nestor, Irache Visiers, Gabriel Weatherhead, Yingchun Ye, Natalie D’Amore
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 inhibition or regression in a human colon tumor (HT29) xenograft model.