Molecular Oncology
Volume 3, Issue 3 , Pages 248-261 , June 2009

Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530

  • Tim P. Green

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • Corresponding Author InformationCorresponding 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

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Robin Whittaker

      Affiliations

    • Clinical Development, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Jon Curwen

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Vivien Jacobs

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Jack Allen

      Affiliations

    • Clinical Pharmacology and DMPK, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Armelle Logie

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Judith Hargreaves

      Affiliations

    • Clinical Pharmacology and DMPK, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • D. Mark Hickinson

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Robert W. Wilkinson

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Paul Elvin

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Brigitte Boyer

      Affiliations

    • Inserm U784, 46 Rue d'Ulm, 75230 Paris, Cedex 05, France
    • ,
  • Neil Carragher

      Affiliations

    • Advanced Science and Technology Laboratory, AstraZeneca R&D, Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK
    • ,
  • Patrick A. Plé

      Affiliations

    • Discovery Enabling Capabilities & Sciences, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Alun Bermingham

      Affiliations

    • 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

      Affiliations

    • Discovery Enabling Capabilities & Sciences, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Walter H.J. Ward

      Affiliations

    • Discovery Enabling Capabilities & Sciences, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Laurent F. Hennequin

      Affiliations

    • 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

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK
    • ,
  • Gerard F. Costello

      Affiliations

    • Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK

Received 7 November 2008 ,Revised 19 January 2009 ,Accepted 20 January 2009.

References 

  1. Avizienyte E, Wyke AW, Jones RJ, McLean GW, Westhoff MA, Brunton VG, et al. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat. Cell Biol. 2002;4:632–638
  2. Bolen JB, Veillette A, Schwartz AM, DeSeau V, Rosen N. Activation of pp60c-src protein kinase activity in human colon carcinoma. Proc. Natl. Acad. Sci. U.S.A. 1987;84:2251–2255
  3. Boyer B, Bourgeois Y, Poupon MF. Src kinase contributes to the metastatic spread of carcinoma cells. Oncogene. 2002;21:2347–2356
  4. Boyer B, Roche S, Denoyelle M, Thiery JP. Src and Ras are involved in separate pathways in epithelial cell scattering. EMBO J. 1997;16:5904–5913
  5. Bridges AJ. Chemical inhibitors of protein kinases. Chem. Rev. 2001;101:2541–2572
  6. Carragher NO, Walker SM, Scott Carragher LA, Harris F, Sawyer TK, Brunton VG, et al. Calpain 2 and Src dependence distinguishes mesenchymal and amoeboid modes of tumour cell invasion: a link to integrin function. Oncogene. 2006;25:5726–5740
  7. Cartwright CA, Eckhart W, Simon S, Kaplan PL. Cell transformation by pp60c-src mutated in the carboxy-terminal regulatory domain. Cell. 1987;49:83–91
  8. Chu I, Sun J, Arnaout A, Kahn H, Hanna W, Narod S, et al. p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. Cell. 2007;128:281–294
  9. Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol. Cell. 1999;4:915–924
  10. Emaduddin M, Bicknell DC, Bodmer WF, Feller SM. Cell growth, global phosphotyrosine elevation, and c-Met phosphorylation through Src family kinases in colorectal cancer cells. Proc. Natl. Acad. Sci. U.S.A. 2008;105:2358–2362
  11. Frame MC. Src in cancer: de-regulation and consequences for cell behaviour. Biochim. Biophys. Acta. 2002;1602:114–130
  12. Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat. Rev. Cancer. 2003;3:362–374
  13. Fu YN, Yeh CL, Cheng HH, Yang CH, Tsai SF, Huang SF, et al. EGFR mutants found in non-small cell lung cancer show different levels of sensitivity to suppression of Src: implications in targeting therapy. Oncogene. 2008;27:957–965
  14. Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003;63:375–381
  15. Green T, Hennequin LF, Ple PA, Jones RJ, Clack G, Gallagher N. Pre-clinical and early clinical activity of the highly selective, orally available, dual Src/Abl kinase inhibitor AZD0530. Proc. Am. Assoc. Cancer Res. 2005;46:abst SY13-3
  16. Helfrich B, Frederick B, Raben D, Bunn PA. The dual-specific Src/Abl kinase inhibitor AZD0530 inhibits in vitro growth and induces apoptosis in non-small-cell lung cancer lines. Eur. J. Cancer. 2006;(Suppl. 4):177
  17. Hennequin LF, Allen J, Breed J, Curwen J, Fennell M, Green TP, et al N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J. Med. Chem. 2006;49:6465–6488
  18. Hiscox S, Morgan L, Green TP, Barrow D, Gee J, Nicholson RI. Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Res. Treat. 2006;97:263–274
  19. Huse M, Kuriyan J. The conformational plasticity of protein kinases. Cell. 2002;109:275–282
  20. Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, et al. Activating SRC mutation in a subset of advanced human colon cancers. Nat. Genet. 1999;21:187–190
  21. Irby RB, Yeatman TJ. Increased Src activity disrupts cadherin/catenin-mediated homotypic adhesion in human colon cancer and transformed rodent cells. Cancer Res. 2002;62:2669–2674
  22. Jenkins WT. The pyruvate kinase-coupled assay for ATPases: a critical analysis. Anal. Biochem. 1991;194:136–139
  23. Jones RJ, Avizienyte E, Wyke AW, Owens DW, Brunton VG, Frame MC. Elevated c-Src is linked to altered cell-matrix adhesion rather than proliferation in KM12C human colorectal cancer cells. Br. J. Cancer. 2002;87:1128–1135
  24. Karlsson R, Kullman-Magnusson M, Hamalainen MD, Remaeus A, Andersson K, Borg P, et al. Biosensor analysis of drug–target interactions: direct and competitive binding assays for investigation of interactions between thrombin and thrombin inhibitors. Anal. Biochem. 2000;278:1–13
  25. Kmiecik TE, Shalloway D. Activation and suppression of pp60c-src transforming ability by mutation of its primary sites of tyrosine phosphorylation. Cell. 1987;49:65–73
  26. Lesslie DP, Gallick GE. Src family kinases as regulators of angiogenesis: therapeutic implications. Curr. Cancer Ther. Rev. 2005;1:45–50
  27. Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem. 2004;47:6658–6661
  28. Lozzio CB, Lozzio BB. Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood. 1975;45:321–334
  29. Manley PW, Cowan-Jacob SW, Mestan J. Advances in the structural biology, design and clinical development of Bcr–Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim. Biophys. Acta. 2005;1754:3–13
  30. Mannervik B. Regression analysis, experimental error, and statistical criteria in the design and analysis of experiments for discrimination between rival kinetic models. Methods Enzymol. 1982;87:370–390
  31. Martin GS. The hunting of the Src. Nat. Rev. Mol. Cell Biol. 2001;2:467–475
  32. Metcalf CA, van Schravendijk MR, Dalgarno DC, Sawyer TK. Targeting protein kinases for bone disease: discovery and development of Src inhibitors. Curr. Pharm. Des. 2002;8:2049–2075
  33. Nam JS, Ino Y, Sakamoto M, Hirohashi S. Src family kinase inhibitor PP2 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis. Clin. Cancer Res. 2002;8:2430–2436
  34. Noble ME, Endicott JA, Johnson LN. Protein kinase inhibitors: insights into drug design from structure. Science. 2004;303:1800–1805
  35. Oneyama C, Hikita T, Nada S, Okada M. Functional dissection of transformation by c-Src and v-Src. Genes Cells. 2008;13:1–12
  36. Phillips KA, Parikh NU, Park SI, Kuwai T, Nokomura T, Green TP, et al. Inhibition of colon tumor metastasis in orthotopic nude mouse models with the dual-selective Src/Abl kinase inhibitor, AZD0530. Mol. Cancer Ther. 2007;6:abst PR-11
  37. Playford MP, Schaller MD. The interplay between Src and integrins in normal and tumor biology. Oncogene. 2004;23:7928–7946
  38. Plé PA, Green TP, Hennequin LF, Curwen J, Fennell M, Allen J, et al. Discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of c-Src. J. Med. Chem. 2004;47:871–887
  39. Rosen N, Bolen JB, Schwartz AM, Cohen P, DeSeau V, Israel MA. Analysis of pp60c-src protein kinase activity in human tumor cell lines and tissues. J. Biol. Chem. 1986;261:13754–13759
  40. Serrels A, Macpherson IR, Evans TR, Lee FY, Clark EA, Sansom OJ, et al. Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib. Mol. Cancer Ther. 2006;5:3014–3022
  41. Shor AC, Keschman EA, Lee FY, Muro-Cacho C, Letson GD, Trent JC, et al. Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival. Cancer Res. 2007;67:2800–2808
  42. Song L, Morris M, Bagui T, Lee FY, Jove R, Haura EB. Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res. 2006;66:5542–5548
  43. Sullivan JE, Holdgate GA, Campbell D, Timms D, Gerhardt S, Breed J, et al Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase. Biochemistry. 2005;44:16475–16490
  44. Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 2003;22:337–358
  45. Talamonti MS, Roh MS, Curley SA, Gallick GE. Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. J. Clin. Invest. 1993;91:53–60
  46. Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu. Rev. Cell Dev. Biol. 1997;13:513–609
  47. Trevino JG, Summy JM, Lesslie DP, Parikh NU, Hong DS, Lee FY, et al. Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am. J. Pathol. 2006;168:962–972
  48. Valles AM, Beuvin M, Boyer B. Activation of Rac1 by paxillin-Crk-DOCK180 signaling complex is antagonized by Rap1 in migrating NBT-II cells. J. Biol. Chem. 2004;279:44490–44496
  49. Vultur A, Buettner R, Kowolik C, Liang W, Smith D, Boschelli F, et al. SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol. Cancer Ther. 2008;7:1185–1194
  50. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, et al AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65:4389–4400
  51. Wilkinson RW, Odedra R, Heaton SP, Wedge SR, Keen NJ, Crafter C, et al AZD1152, a selective inhibitor of aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin. Cancer Res. 2007;13:3682–3688
  52. Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, et al. Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 2003;160:267–277

PII: S1574-7891(09)00018-0

doi: 10.1016/j.molonc.2009.01.002

Molecular Oncology
Volume 3, Issue 3 , Pages 248-261 , June 2009

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