A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo.
Insulin-like growth factor-I receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non-small cell lung, ovarian, and pediatric cancers, which may drive their own growth and survival through autocrine IGF-II expression, the role of IGF-IR is especially critical. Here, we present a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which displayed a cellular IC(50) of 19 nmol/L for inhibition of ligand-dependent autophosphorylation of human IGF-IR with 14-fold cellular selectivity relative to the human insulin receptor. PQIP showed minimal activity against a panel of 32 other protein kinases. It also abolished the ligand-induced activation of downstream phosphorylated AKT and phosphorylated extracellular signal-regulated kinase 1/2 in both IGF-IR transfectant cells and a GEO human colorectal cancer cell line. Analysis of GEO cells revealed a significant level of both phosphorylated IGF-IR and IGF-II expression. Furthermore, inactivation of IGF-II in conditioned GEO culture medium by a neutralizing antibody diminished IGF-IR activation, indicating the presence of a functional IGF-II/IGF-IR autocrine loop in GEO cells. Once daily oral dosing of PQIP induced robust antitumor efficacy in GEO xenografts. The antitumor efficacy correlated with the degree and duration of inhibition of tumor IGF-IR phosphorylation in vivo by this compound. Moreover, when mice were treated for 3 days with a dose of PQIP that maximally inhibited tumor growth, only minor changes in blood glucose were observed. Thus, PQIP represents a potent and selective IGF-IR kinase inhibitor that is especially efficacious in an IGF-II-driven human tumor model.
Oncology, OSI Pharmaceuticals, Inc., New York, New York, USA. qji@osip.com
Qun-sheng
QS
Ji
Mark J
MJ
Mulvihill
Maryland
M
Rosenfeld-Franklin
Andrew
A
Cooke
Lixin
L
Feng
Gilda
G
Mak
Matthew
M
O'Connor
Yan
Y
Yao
Caroline
C
Pirritt
Elizabeth
E
Buck
Alexandra
A
Eyzaguirre
Lee D
LD
Arnold
Neil W
NW
Gibson
Jonathan A
JA
Pachter
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019898:Autocrine Communication / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
C523453:3-(3-(4-methylpiperazin-1-yl)cyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-8-ylamine; D000970:Antineoplastic Agents; D001786:Blood Glucose; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1