Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor.
ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 micromol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-beta, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED50 = 1.5-5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC50 corrected for plasma protein binding = 0.08 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer.
Albert
Daniel H
DH
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R47J, Building AP9/2, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. daniel.h.albert@abbott.com
Tapang
Paul
P
Magoc
Terrance J
TJ
Pease
Lori J
LJ
Reuter
David R
DR
Wei
Ru-Qi
RQ
Li
Junling
J
Guo
Jun
J
Bousquet
Peter F
PF
Ghoreishi-Haack
Nayereh S
NS
Wang
Baole
B
Bukofzer
Gail T
GT
Wang
Yi-Chun
YC
Stavropoulos
Jason A
JA
Hartandi
Kresna
K
Niquette
Amanda L
AL
Soni
Nirupama
N
Johnson
Eric F
EF
McCall
J Owen
JO
Bouska
Jennifer J
JJ
Luo
Yanping
Y
Donawho
Cherrie K
CK
Dai
Yujia
Y
Marcotte
Patrick A
PA
Glaser
Keith B
KB
Michaelides
Michael R
MR
Davidsen
Steven K
SK
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003315:Cornea; D004487:Edema; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007191:Indazoles / Q000494:pharmacology*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology; D014599:Uterus / Q000187:drug effects / Q000503:physiopathology
D004791:Enzyme Inhibitors; D007191:Indazoles; D010671:Phenylurea Compounds; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor