title: GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers.
abstract: The insulin-like growth factor-I receptor (IGF-IR) signaling pathway is activated in various tumors, and inhibition of IGF-IR kinase provides a therapeutic opportunity in these patients. GSK1838705A is a small-molecule kinase inhibitor that inhibits IGF-IR and the insulin receptor with IC(50)s of 2.0 and 1.6 nmol/L, respectively. GSK1838705A blocks the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing's sarcoma, and retards the growth of human tumor xenografts in vivo. Despite the inhibitory effect of GSK1838705A on insulin receptor, minimal effects on glucose homeostasis were observed at efficacious doses. GSK1838705A also inhibits the anaplastic lymphoma kinase (ALK), which drives the aberrant growth of anaplastic large-cell lymphomas, some neuroblastomas, and a subset of non-small cell lung cancers. GSK1838705A inhibits ALK, with an IC(50) of 0.5 nmol/L, and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses. GSK1838705A is therefore a promising antitumor agent for therapeutic use in human cancers.
authors.affiliation: Oncology R&D, Cancer Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Susan
authors.initials: S
authors.lastname: Korenchuk
authors.forename: Jason L
authors.initials: JL
authors.lastname: Rowand
authors.forename: Arthur
authors.initials: A
authors.lastname: Groy
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Dominic
authors.initials: D
authors.lastname: Leperi
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: Ryan G
authors.initials: RG
authors.lastname: Kruger
authors.forename: Richard R
authors.initials: RR
authors.lastname: Gontarek
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Maksimchuk
authors.forename: Sapna
authors.initials: S
authors.lastname: Suravajjala
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lapierre
authors.forename: J Brad
authors.initials: JB
authors.lastname: Shotwell
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Wilson
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Chamberlain
authors.forename: Sridhar K
authors.initials: SK
authors.lastname: Rabindran
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; C546191:GSK 1838705A; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin