Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment.
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.
Mayer
Scott C
SC
Wyeth Research, Chemical & Screening Sciences, 865 Ridge Road, Monmouth Junction, Princeton, NJ 08852, USA. mayers@wyeth.com
Banker
Annette L
AL
Boschelli
Frank
F
Di
Li
L
Johnson
Mark
M
Kenny
Cynthia Hess
CH
Krishnamurthy
Girija
G
Kutterer
Kristina
K
Moy
Franklin
F
Petusky
Susan
S
Ravi
Malini
M
Tkach
Diane
D
Tsou
Hwei-Ru
HR
Xu
Weixin
W
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
D000970:Antineoplastic Agents; D007546:Isoquinolines; D054852:Small Molecule Libraries; D017526:Receptor, IGF Type 1