Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530

Green, Tim P.; Fennell, Mike; Whittaker, Robin; Curwen, Jon; Jacobs, Vivien; Allen, Jack; Logie, Armelle; Hargreaves, Judith; Hickinson, D. Mark; Wilkinson, Robert W.; Elvin, Paul; Boyer, Brigitte; Carragher, Neil; Plé, Patrick A.; Bermingham, Alun; Holdgate, Geoffrey A.; Ward, Walter H.J.; Hennequin, Laurent F.; Davies, Barry R.; Costello, Gerard F.

doi:10.1016/j.molonc.2009.01.002

« Previous Next »Molecular Oncology
Volume 3, Issue 3 , Pages 248-261, June 2009

Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530

Tim P. Green
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
- Corresponding author. c/o Paul Elvin, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Tel.: +44 1625 516 178; fax: +44 1625 510 097.
Mike Fennell
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Robin Whittaker
- Clinical Development, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Jon Curwen
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Vivien Jacobs
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Jack Allen
- Clinical Pharmacology and DMPK, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Armelle Logie
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Judith Hargreaves
- Clinical Pharmacology and DMPK, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
D. Mark Hickinson
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Robert W. Wilkinson
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Paul Elvin
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Brigitte Boyer
- Inserm U784, 46 Rue d'Ulm, 75230 Paris, Cedex 05, France
Neil Carragher
- Advanced Science and Technology Laboratory, AstraZeneca R&D, Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK
Patrick A. Plé
- Discovery Enabling Capabilities & Sciences, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Alun Bermingham
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
- Present address: Molecular Targets Development Program, National Cancer Institute, Building 562, Fort Detrick, Frederick, MD 21702-1201, USA.
Geoffrey A. Holdgate
- Discovery Enabling Capabilities & Sciences, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Walter H.J. Ward
- Discovery Enabling Capabilities & Sciences, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Laurent F. Hennequin
- Cancer and Infection Research Area Reims, AstraZeneca, Centre de Recherches, Z.I. La Pompelle B.P. 1050, 51689 Reims Cedex 2, France
Barry R. Davies
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
Gerard F. Costello
- Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK

Received 7 November 2008; received in revised form 19 January 2009; accepted 20 January 2009. published online 09 February 2009.

Abstract

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 (IC₅₀ 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.