title: AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer.
abstract: Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a promising therapeutic approach that aims to stabilize the progression of solid malignancies by abrogating tumor-induced angiogenesis. This may be accomplished by inhibiting the kinase activity of VEGF receptor-2 (KDR), which has a key role in mediating VEGF-induced responses. The novel indole-ether quinazoline AZD2171 is a highly potent (IC50 < 1 nmol/L) ATP-competitive inhibitor of recombinant KDR tyrosine kinase in vitro. Concordant with this activity, in human umbilical vein endothelial cells, AZD2171 inhibited VEGF-stimulated proliferation and KDR phosphorylation with IC50 values of 0.4 and 0.5 nmol/L, respectively. In a fibroblast/endothelial cell coculture model of vessel sprouting, AZD2171 also reduced vessel area, length, and branching at subnanomolar concentrations. Once-daily oral administration of AZD2171 ablated experimental (VEGF-induced) angiogenesis in vivo and inhibited endochondral ossification in bone or corpora luteal development in ovary; physiologic processes that are highly dependent upon neovascularization. The growth of established human tumor xenografts (colon, lung, prostate, breast, and ovary) in athymic mice was inhibited dose-dependently by AZD2171, with chronic administration of 1.5 mg per kg per day producing statistically significant inhibition in all models. A histologic analysis of Calu-6 lung tumors treated with AZD2171 revealed a reduction in microvessel density within 52 hours that became progressively greater with the duration of treatment. These changes are indicative of vascular regression within tumors. Collectively, the data obtained with AZD2171 are consistent with potent inhibition of VEGF signaling, angiogenesis, neovascular survival, and tumor growth. AZD2171 is being developed clinically as a once-daily oral therapy for the treatment of cancer.
authors.affiliation: Cancer Bioscience, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom. steve.wedge@astrazeneca.com
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
authors.forename: Jane
authors.initials: J
authors.lastname: Kendrew
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Hennequin
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Valentine
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Brave
authors.forename: Neil R
authors.initials: NR
authors.lastname: Smith
authors.forename: Neil H
authors.initials: NH
authors.lastname: James
authors.forename: Michael
authors.initials: M
authors.lastname: Dukes
authors.forename: Jon O
authors.initials: JO
authors.lastname: Curwen
authors.forename: Rosemary
authors.initials: R
authors.lastname: Chester
authors.forename: Janet A
authors.initials: JA
authors.lastname: Jackson
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Boffey
authors.forename: Lyndsey L
authors.initials: LL
authors.lastname: Kilburn
authors.forename: Sharon
authors.initials: S
authors.lastname: Barnett
authors.forename: Graham H P
authors.initials: GH
authors.lastname: Richmond
authors.forename: Peter F
authors.initials: PF
authors.lastname: Wadsworth
authors.forename: Mike
authors.initials: M
authors.lastname: Walker
authors.forename: Alison L
authors.initials: AL
authors.lastname: Bigley
authors.forename: Sian T
authors.initials: ST
authors.lastname: Taylor
authors.forename: Lee
authors.initials: L
authors.lastname: Cooper
authors.forename: Sarah
authors.initials: S
authors.lastname: Beck
authors.forename: Juliane M
authors.initials: JM
authors.lastname: Jürgensmeier
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Ogilvie
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001846:Bone Development / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003338:Corpus Luteum / Q000187:drug effects / Q000254:growth & development; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D005260:Female; D006801:Humans; D051379:Mice; D018995:Myosin Heavy Chains; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D024501:Nonmuscle Myosin Type IIB; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D016326:Extracellular Matrix Proteins; D018995:Myosin Heavy Chains; D024501:Nonmuscle Myosin Type IIB; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; C103815:nonmuscle myosin type IIB heavy chain; C500926:cediranib; D007211:Indoles