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

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

  • J Med Chem. 2012 Jan 12;55(1):197-208. doi: 10.1021/jm2011172.
Matthew O Duffey 1 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
Affiliations

Affiliation

  • 1 Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States. matthew.duffey@mpi.com
Abstract

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.

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