title: Synthesis and structure-activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors.
abstract: The Cell division cycle 7 (Cdc7) protein kinase is essential for DNA replication and maintenance of genome stability. We systematically explored thiazole-based compounds as inhibitors of Cdc7 kinase activity in cancer cells. Our studies resulted in the identification of a potent, selective Cdc7 inhibitor that decreased phosphorylation of the direct substrate MCM2 in vitro and in vivo, and inhibited DNA synthesis and cell viability in vitro.
authors.affiliation: Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: Andreas.Reichelt@amgen.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichelt
authors.affiliation: Oncology Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Bailis
authors.affiliation: Molecular Structure and Characterization, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.affiliation: Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Guomin
authors.initials: G
authors.lastname: Yao
authors.affiliation: Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Shu
authors.affiliation: Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Kaller
authors.affiliation: Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Allen
authors.affiliation: Oncology Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Weidner
authors.affiliation: Oncology Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Keegan
authors.affiliation: Molecular Structure and Characterization, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Dao
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D064111:Minichromosome Maintenance Complex Component 2 / Q000378:metabolism; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2
keywords: Cdc7; DNA replication; Kinase inhibitor; MCM2; Thiazole