2. Academic Validation
  3. 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. [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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