title: Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment.
abstract: Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. This receptor is over-expressed or activated in tumor cells and is emerging as a novel target in cancer therapy. Efforts in our "Hit to Lead" group have generated a novel series of submicromolar IGF-1R inhibitors based on a isoquinolinedione template originating from a Lance enzyme HTS screen. Chemical triage and parallel synthesis incorporating focused library arrays were instrumental in moving these investigations through the Wyeth exploratory medicinal chemistry process. The strategies, synthesis, and SAR behind this interesting kinase scaffold will be described.
authors.affiliation: Wyeth Research, Chemical & Screening Sciences, 865 Ridge Road, Monmouth Junction, Princeton, NJ 08852, USA. mayers@wyeth.com
authors.forename: Scott C
authors.initials: SC
authors.lastname: Mayer
authors.forename: Annette L
authors.initials: AL
authors.lastname: Banker
authors.forename: Frank
authors.initials: F
authors.lastname: Boschelli
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.forename: Cynthia Hess
authors.initials: CH
authors.lastname: Kenny
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: Kristina
authors.initials: K
authors.lastname: Kutterer
authors.forename: Franklin
authors.initials: F
authors.lastname: Moy
authors.forename: Susan
authors.initials: S
authors.lastname: Petusky
authors.forename: Malini
authors.initials: M
authors.lastname: Ravi
authors.forename: Diane
authors.initials: D
authors.lastname: Tkach
authors.forename: Hwei-Ru
authors.initials: HR
authors.lastname: Tsou
authors.forename: Weixin
authors.initials: W
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; D054852:Small Molecule Libraries; D017526:Receptor, IGF Type 1