title: Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605.
abstract: BACKGROUND
  The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics.
  
  
  METHODS
  We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers.
  
  
  RESULTS
  A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models.
  
  
  CONCLUSIONS
  These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation.
authors.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. bill.pappano@abbott.com
authors.forename: William N
authors.initials: WN
authors.lastname: Pappano
authors.forename: Paul M
authors.initials: PM
authors.lastname: Jung
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Meulbroek
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Robert D
authors.initials: RD
authors.lastname: Hubbard
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Meagan M
authors.initials: MM
authors.lastname: Grudzien
authors.forename: Niru B
authors.initials: NB
authors.lastname: Soni
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
authors.forename: Cherrie
authors.initials: C
authors.lastname: Donawho
authors.forename: Fritz G
authors.initials: FG
authors.lastname: Buchanan
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Randy L
authors.initials: RL
authors.lastname: Bell
authors.forename: Jieyi
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D017451:Receptors, Somatomedin; C014175:pyrazolo(3,4-d)pyrimidine