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
  • 1. Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States. [email protected]
PMID: 22070629 DOI: 10.1021/jm2011172
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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