title: Antitumor activity of GSK1904529A, a small-molecule inhibitor of the insulin-like growth factor-I receptor tyrosine kinase.
abstract: OBJECTIVE
  Dysregulation of the insulin-like growth factor-I receptor (IGF-IR) signaling pathway has been implicated in the development of many types of tumors, including prostate, colon, breast, pancreatic, ovarian, and sarcomas. Agents that inhibit IGF-IR activity may be useful in treatment of patients with various cancers.
  
  
  METHODS
  Kinase assays were used to identify a selective small-molecule inhibitor of IGF-IR activity. The effects of this compound on IGF-IR signaling, cell proliferation, and the cell cycle were determined using a panel of cell lines. Antitumor activity was evaluated in human tumor xenografts growing in athymic mice. Inhibition of IGF-IR and the closely related insulin receptor (IR) was measured in vivo, and the effect on glucose metabolism was evaluated.
  
  
  RESULTS
  GSK1904529A selectively inhibits IGF-IR and IR with IC(50)s of 27 and 25 nmol/L, respectively. GSK1904529A blocks receptor autophosphorylation and downstream signaling, leading to cell cycle arrest. It inhibits the proliferation of cell lines derived from solid and hematologic malignancies, with multiple myeloma and Ewing's sarcoma cell lines being most sensitive. Oral administration of GSK1904529A decreases the growth of human tumor xenografts in mice, consistent with a reduction of IGF-IR phosphorylation in tumors. Despite the potent inhibitory activity of GSK1904529A on IR in vitro and in vivo, minimal effects on blood glucose levels are observed in animals at doses that show significant antitumor activity.
  
  
  CONCLUSIONS
  GSK1904529A is a promising candidate for therapeutic use in IGF-IR-dependent tumors.
authors.affiliation: GlaxoSmithKline, Oncology R&D, Collegeville, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Jason L
authors.initials: JL
authors.lastname: Rowand
authors.forename: Arthur
authors.initials: A
authors.lastname: Groy
authors.forename: Susan
authors.initials: S
authors.lastname: Korenchuk
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Charity
authors.initials: C
authors.lastname: Atkins
authors.forename: Melissa
authors.initials: M
authors.lastname: Dumble
authors.forename: Jingsong
authors.initials: J
authors.lastname: Yang
authors.forename: Kelly
authors.initials: K
authors.lastname: Anderson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wilson
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Emmitte
authors.forename: Sridhar K
authors.initials: SK
authors.lastname: Rabindran
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; C000607695:GSK1904529A; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D020155:3-Hydroxybutyric Acid