title: N-substituted azaindoles as potent inhibitors of Cdc7 kinase.
abstract: Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series.
authors.affiliation: Medicinal Chemistry Research Technologies, Therapeutic Discovery, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Bryan
authors.forename: James R
authors.initials: JR
authors.lastname: Falsey
authors.forename: Mike
authors.initials: M
authors.lastname: Frohn
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichelt
authors.forename: Guomin
authors.initials: G
authors.lastname: Yao
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Julie M
authors.initials: JM
authors.lastname: Bailis
authors.forename: Leeanne
authors.initials: L
authors.lastname: Zalameda
authors.forename: Tisha San
authors.initials: TS
authors.lastname: Miguel
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: John G
authors.initials: JG
authors.lastname: Allen
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C512290:5-azaindole; D001372:Aza Compounds; D018797:Cell Cycle Proteins; D007211:Indoles; D047428:Protein Kinase Inhibitors; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases