title: Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905).
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.
authors: Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States. matthew.duffey@mpi.com
authors: Matthew O
authors: MO
authors: Duffey
authors: Tricia J
authors: TJ
authors: Vos
authors: Ruth
authors: R
authors: Adams
authors: Jennifer
authors: J
authors: Alley
authors: Justin
authors: J
authors: Anthony
authors: Cynthia
authors: C
authors: Barrett
authors: Indu
authors: I
authors: Bharathan
authors: Douglas
authors: D
authors: Bowman
authors: Nancy J
authors: NJ
authors: Bump
authors: Ryan
authors: R
authors: Chau
authors: Courtney
authors: C
authors: Cullis
authors: Denise L
authors: DL
authors: Driscoll
authors: Amy
authors: A
authors: Elder
authors: Nancy
authors: N
authors: Forsyth
authors: Jonathan
authors: J
authors: Frazer
authors: Jianping
authors: J
authors: Guo
authors: Luyi
authors: L
authors: Guo
authors: Marc L
authors: ML
authors: Hyer
authors: David
authors: D
authors: Janowick
authors: Bheemashankar
authors: B
authors: Kulkarni
authors: Su-Jen
authors: SJ
authors: Lai
authors: Kerri
authors: K
authors: Lasky
authors: Gang
authors: G
authors: Li
authors: Jing
authors: J
authors: Li
authors: Debra
authors: D
authors: Liao
authors: Jeremy
authors: J
authors: Little
authors: Bo
authors: B
authors: Peng
authors: Mark G
authors: MG
authors: Qian
authors: Dominic J
authors: DJ
authors: Reynolds
authors: Mansoureh
authors: M
authors: Rezaei
authors: Margaret Porter
authors: MP
authors: Scott
authors: Todd B
authors: TB
authors: Sells
authors: Vaishali
authors: V
authors: Shinde
authors: Qiuju Judy
authors: QJ
authors: Shi
authors: Michael D
authors: MD
authors: Sintchak
authors: Francois
authors: F
authors: Soucy
authors: Kevin T
authors: KT
authors: Sprott
authors: Stephen G
authors: SG
authors: Stroud
authors: Michelle
authors: M
authors: Nestor
authors: Irache
authors: I
authors: Visiers
authors: Gabriel
authors: G
authors: Weatherhead
authors: Yingchun
authors: Y
authors: Ye
authors: Natalie
authors: N
authors: D'Amore
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014183:Transplantation, Heterologous; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; D018797:Cell Cycle Proteins; D007769:Lactams; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013871:Thiones; D000097869:Polo-Like Kinase 1; C570910:9-trifluoromethyl-2-((5-(3-(dimethylamino)propyl)-2-methylpyridin-3-yl)amino)-5,7-dihydro-6H-pyrimido(5,4-d)(1)benzazepine-6-thione