Development of multitargeted inhibitors of both the insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor family of receptor tyrosine kinases

Robert D Hubbard; Nwe Y Bamaung; Steve D Fidanze; Scott A Erickson; Fabio Palazzo; Julie L Wilsbacher; Qian Zhang; Lora A Tucker; Xiaoming Hu; Peter Kovar; Donald J Osterling; Eric F Johnson; Jennifer Bouska; Jieyi Wang; Steven K Davidsen; Randy L Bell; George S Sheppard

doi:10.1016/j.bmcl.2009.01.086

Development of multitargeted inhibitors of both the insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor family of receptor tyrosine kinases

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1718-21. doi: 10.1016/j.bmcl.2009.01.086. Epub 2009 Jan 30.

Authors

Robert D Hubbard¹, Nwe Y Bamaung, Steve D Fidanze, Scott A Erickson, Fabio Palazzo, Julie L Wilsbacher, Qian Zhang, Lora A Tucker, Xiaoming Hu, Peter Kovar, Donald J Osterling, Eric F Johnson, Jennifer Bouska, Jieyi Wang, Steven K Davidsen, Randy L Bell, George S Sheppard

Affiliation

¹ Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.

PMID: 19217287
DOI: 10.1016/j.bmcl.2009.01.086

Abstract

Emerging clinical and pre-clinical data indicate that both insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs) exhibit significant cross-talk in human cancers. Therefore, a small molecule that successfully inhibits the signaling of both classes of oncogenic kinases might provide an attractive agent for chemotherapeutic use. Herein, we disclose the structure activity relationships that led to the synthesis and biological characterization of 14, a novel small molecule inhibitor of both IGF-IR and members of the epidermal growth factor family of RTKs.

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Chemistry, Pharmaceutical / methods*
Dimerization
Drug Design
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism*
Humans
Lung / metabolism
Models, Chemical
Neoplasms / metabolism
Phosphorylation
Pyrimidines / chemistry
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / chemistry
Receptors, Somatomedin / antagonists & inhibitors*
Receptors, Somatomedin / metabolism*
Signal Transduction

Substances

Antineoplastic Agents
Pyrimidines
Receptors, Somatomedin
ErbB Receptors
Receptor Protein-Tyrosine Kinases
pyrimidine