title: 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.
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.
authors.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Hubbard
authors.forename: Nwe Y
authors.initials: NY
authors.lastname: Bamaung
authors.forename: Steve D
authors.initials: SD
authors.lastname: Fidanze
authors.forename: Scott A
authors.initials: SA
authors.lastname: Erickson
authors.forename: Fabio
authors.initials: F
authors.lastname: Palazzo
authors.forename: Julie L
authors.initials: JL
authors.lastname: Wilsbacher
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lora A
authors.initials: LA
authors.lastname: Tucker
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Osterling
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Jieyi
authors.initials: J
authors.lastname: Wang
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Randy L
authors.initials: RL
authors.lastname: Bell
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D017451:Receptors, Somatomedin; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C030986:pyrimidine