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.
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.
Hubbard
Robert D
RD
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
Bamaung
Nwe Y
NY
Fidanze
Steve D
SD
Erickson
Scott A
SA
Palazzo
Fabio
F
Wilsbacher
Julie L
JL
Zhang
Qian
Q
Tucker
Lora A
LA
Hu
Xiaoming
X
Kovar
Peter
P
Osterling
Donald J
DJ
Johnson
Eric F
EF
Bouska
Jennifer
J
Wang
Jieyi
J
Davidsen
Steven K
SK
Bell
Randy L
RL
Sheppard
George S
GS
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019281:Dimerization; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism; D008956:Models, Chemical; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D011743:Pyrimidines / Q000737:chemistry; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D011743:Pyrimidines; D017451:Receptors, Somatomedin; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C030986:pyrimidine