title: Identification of novel, potent and selective inhibitors of Polo-like kinase 1.
abstract: A series of pyrimidodiazepines was identified as potent Polo-like kinase 1 (PLK1) inhibitors. The synthesis and SAR are discussed. The lead compound 7 (RO3280) has potent inhibitory activity against PLK1, good selectivity against other kinases, and excellent in vitro cellular potency. It showed strong antitumor activity in xenograft mouse models.
authors.affiliation: Discovery Chemistry, Hoffmann-La Roche Inc., Pharma Research & Early Development, Small Molecule Research, 340 Kingsland Street, Nutley, NJ 07110, United States. shaoqing.chen@roche.com
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Bartkovitz
authors.forename: Jianping
authors.initials: J
authors.lastname: Cai
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.forename: Xin-Jie
authors.initials: XJ
authors.lastname: Chu
authors.forename: Kang
authors.initials: K
authors.lastname: Le
authors.forename: Nam T
authors.initials: NT
authors.lastname: Le
authors.forename: Kin-Chun
authors.initials: KC
authors.lastname: Luk
authors.forename: Steve
authors.initials: S
authors.lastname: Mischke
authors.forename: Goli
authors.initials: G
authors.lastname: Naderi-Oboodi
authors.forename: John F
authors.initials: JF
authors.lastname: Boylan
authors.forename: Tom
authors.initials: T
authors.lastname: Nevins
authors.forename: Weiguo
authors.initials: W
authors.lastname: Qing
authors.forename: Yingsi
authors.initials: Y
authors.lastname: Chen
authors.forename: Peter M
authors.initials: PM
authors.lastname: Wovkulich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000097869:Polo-Like Kinase 1; C000601179:RO3280