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

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• 作者：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鈥橝more
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 12, 2012
• 年：2012
• 卷：55
• 期：1
• 页码：197-208
• 全文大小：467K
• 年卷期：v.55,no.1(January 12, 2012)
• ISSN：1520-4804

文摘

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鈥損harmacodynamic 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.