GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers.
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.
Sabbatini
Peter
P
Oncology R&D, Cancer Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
Korenchuk
Susan
S
Rowand
Jason L
JL
Groy
Arthur
A
Liu
Qi
Q
Leperi
Dominic
D
Atkins
Charity
C
Dumble
Melissa
M
Yang
Jingsong
J
Anderson
Kelly
K
Kruger
Ryan G
RG
Gontarek
Richard R
RR
Maksimchuk
Kenneth R
KR
Suravajjala
Sapna
S
Lapierre
Russell R
RR
Shotwell
J Brad
JB
Wilson
Joseph W
JW
Chamberlain
Stanley D
SD
Rabindran
Sridhar K
SK
Kumar
Rakesh
R
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
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