Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530.
AZD0530, an orally available Src inhibitor, demonstrated potent antimigratory and anti-invasive effects in vitro, and inhibited metastasis in a murine model of bladder cancer. Antiproliferative activity of AZD0530 in vitro varied between cell lines (IC(50) 0.2 ->10μM). AZD0530 inhibited tumor growth in 4/10 xenograft models tested and dynamically inhibited in vivo phosphorylation of Src substrates paxillin and FAK in both growth-inhibition-resistant and -sensitive xenografts. The activity of AZD0530 in NBT-II bladder cancer cells in vitro was consistent with inhibition of cell migration and stabilization of cell-cell adhesion. These data suggest a dominant anti-invasive pharmacology for AZD0530 that may limit tumor progression in a range of cancers. AZD0530 is currently in Phase II clinical trials.
Green
Tim P
TP
Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK. timgreen350@googlemail.com
Fennell
Mike
M
Whittaker
Robin
R
Curwen
Jon
J
Jacobs
Vivien
V
Allen
Jack
J
Logie
Armelle
A
Hargreaves
Judith
J
Hickinson
D Mark
DM
Wilkinson
Robert W
RW
Elvin
Paul
P
Boyer
Brigitte
B
Carragher
Neil
N
Plé
Patrick A
PA
Bermingham
Alun
A
Holdgate
Geoffrey A
GA
Ward
Walter H J
WH
Hennequin
Laurent F
LF
Davies
Barry R
BR
Costello
Gerard F
GF
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009368:Neoplasm Transplantation; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D052117:Benzodioxoles; D009363:Neoplasm Proteins; C496061:PXN protein, human; D051419:Paxillin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases