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: Scott C Mayer, Annette L Banker, Frank Boschelli, Li Di, Mark Johnson, Cynthia Hess Kenny, Girija Krishnamurthy, Kristina Kutterer, Franklin Moy, Susan Petusky, Malini Ravi, Diane Tkach, Hwei-Ru Tsou, Weixin Xu
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 12 Pg. 3641-5 (Jun 15 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18501599 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Isoquinolines
• Small Molecule Libraries
• Receptor, IGF Type 1

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Isoquinolines (chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Receptor, IGF Type 1 (antagonists & inhibitors)
• Small Molecule Libraries
• Structure-Activity Relationship