Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451.
CP-673,451 is a potent inhibitor of platelet-derived growth factor beta-receptor (PDGFR-beta) kinase- and PDGF-BB-stimulated autophosphorylation of PDGFR-beta in cells (IC(50) = 1 nmol/L) being more than 450-fold selective for PDGFR-beta versus other angiogenic receptors (e.g., vascular endothelial growth factor receptor 2, TIE-2, and fibroblast growth factor receptor 2). Multiple models have been used to evaluate in vivo activity of CP-673,451 and to understand the pharmacology of PDGFR-beta inhibition and the effect on tumor growth. These models include an ex vivo measure of PDGFR-beta phosphorylation in glioblastoma tumors, a sponge model to measure inhibition of angiogenesis, and multiple models of tumor growth inhibition. Inhibition of PDGFR-beta phosphorylation in tumors correlates with plasma and tumor levels of CP-673,451. A dose of 33 mg/kg was adequate to provide >50% inhibition of receptor for 4 hours corresponding to an EC(50) of 120 ng/mL in plasma at C(max). In a sponge angiogenesis model, CP-673,451 inhibited 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg (q.d. x 5, p.o., corresponding to 5.5 ng/mL at C(max)). The compound did not inhibit vascular endothelial growth factor- or basic fibroblast growth factor-induced angiogenesis at concentrations which inhibited tumor growth. The antitumor efficacy of CP-673,451 was evaluated in a number of human tumor xenografts grown s.c. in athymic mice, including H460 human lung carcinoma, Colo205 and LS174T human colon carcinomas, and U87MG human glioblastoma multiforme. Once-daily p.o. x 10 days dosing routinely inhibited tumor growth (ED(50) < or = 33 mg/kg). These data show that CP-673,451 is a pharmacologically selective PDGFR inhibitor, inhibits tumor PDGFR-beta phosphorylation, selectively inhibits PDGF-BB-stimulated angiogenesis in vivo, and causes significant tumor growth inhibition in multiple human xenograft models.
Roberts
W Gregory
WG
Pfizer Oncology, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. robertswg@groton.pfizer.com
Whalen
Pamela M
PM
Soderstrom
Erik
E
Moraski
Garrett
G
Lyssikatos
Joseph P
JP
Wang
Huifen-F
HF
Cooper
Beth
B
Baker
Deborah A
DA
Savage
Douglas
D
Dalvie
Deepak
D
Atherton
James A
JA
Ralston
Sherry
S
Szewc
Ruby
R
Kath
John C
JC
Lin
Jing
J
Soderstrom
Cathy
C
Tkalcevic
George
G
Cohen
Bruce D
BD
Pollack
Vince
V
Barth
Wayne
W
Hungerford
Will
W
Ung
Ethan
E
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000077214:Becaplermin; D001562:Benzimidazoles / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D017239:Paclitaxel / Q000008:administration & dosage; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C497448:CP-673,451; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011804:Quinolines; D000077214:Becaplermin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017239:Paclitaxel