NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis

Cancer Research - Tập 68 Số 8 - Trang 2850-2860 - 2008
Suzanne A. Eccles1, Andy Massey2, Florence I. Raynaud1, Swee Y. Sharp1, Gary Box1, Melanie Valenti1, Lisa Patterson1, Alexis de Haven Brandon1, Sharon Gowan1, Frances Boxall1, Wynne Aherne1, Martin Rowlands1, Angela Hayes1, Vanessa Martins1, Frederique Urban1, Kathy Boxall1, Chrisostomos Prodromou3, Laurence H. Pearl3, Karen James1, Thomas P. Matthews1, Kung-Kai Cheung1, Andrew Kalusa1, Keith Jones1, Edward McDonald1, Xavier Barril2, Paul A. Brough2, Julie E. Cansfield2, Brian Dymock2, Martin J. Drysdale2, Harry Finch2, Rob Howes2, Roderick E. Hubbard2, Alan Surgenor2, Paul Webb2, Mike Wood2, Lisa Wright2, Paul Workman1
11Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom;
23Vernalis Ltd., Cambridge, United Kingdom
32Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom; and

Tóm tắt

Abstract We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (Kd = 1.7 nmol/L) and proliferation of human tumor cells with GI50 values of approximately 2 to 40 nmol/L, inducing G1-G2 arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI50. This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1α, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials. [Cancer Res 2008;68(8):2850–60]

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Tài liệu tham khảo

Sharp S, Workman P. Inhibitors of the HSP90 molecular chaperone: current status. Adv Cancer Res 2006; 95: 323–8.

Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer 2005; 5: 761–72.

Workman P, Burrows F, Neckers L, Rosen N. Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci 2007; 1113: 202–16.

Pearl LH, Prodromou C. Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 2006; 75: 271–94.

Chiosis G. Targeting chaperones in transformed systems—a focus on Hsp90 and cancer. Expert Opin Ther Targets 2006; 10: 37–50.

Xu W, Neckers L. Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signalling pathways of cancer cells. Clin Cancer Res 2007; 13: 1625–9.

Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 2003; 425: 407–10.

Mosser DD, Morimoto RI. Molecular chaperones and the stress of oncogenesis. Oncogene 2004; 23: 2907–18.

Pick E, Kluger Y, Giltnane JM, et al. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res 2007; 67: 2932–7.

da Rocha Dias S, Friedlos F, Light Y, Springer C, Workman P, Marais R. Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res 2005; 65: 10686–91.

Grbovic OM, Basso AD, Sawai A, et al. V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc Natl Acad Sci U S A 2006; 103: 57–62.

Ge J, Normant E, Porter JR, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 2006; 49: 4606–15.

Sausville EA, Tomaszewski JE, Ivy P. Clinical development of 17-allylamino, 17-demethoxygeldanamycin. Curr Cancer Drug Targets 2003; 3: 377–83.

Banerji U, O'Donnell A, Scurr M, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 2005; 23: 4152–61.

Pacey S, Banerji U, Judson I, Workman P. Hsp90 inhibitors in the clinic. Handbook Exp Pharmacol 2006; 172: 331–58.

Modi S, Stopeck AT, Gordon MS, et al. Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. J Clin Oncol 2007; 25: 5410–7.

Egorin MJ, Rosen DM, Wolff JH, Callery PS, Musser SM, Eiseman JL. Metabolism of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations. Cancer Res 1998; 58: 2385–96.

Kelland LR, Sharp SY, Rogers PM, Myers TG, Workman P. DT-diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J Natl Cancer Inst 1999; 91: 1940–9.

Banerji U, Walton M, Raynaud F, et al. Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models. Clin Cancer Res 2005; 11: 7023–32.

Maloney A, Clarke PA, Naaby-Hansen S, et al. Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res 2007; 67: 3239–53.

Eustace BK, Sakurai T, Stewart JK, et al. Functional proteomic screens reveal an essential extracellular role for hsp90α in cancer cell invasiveness. Nat Cell Biol 2004; 6: 507–14.

Xie Q, Gao CF, Shinomiya N, et al. Geldanamycins exquisitely inhibit HGF/SF-mediated tumor cell invasion. Oncogene 2005; 24: 3697–707.

Sanderson S, Valenti M, Gowan S, et al. Benzoquinone ansamycin heat shock protein 90 inhibitors modulate multiple functions required for tumor angiogenesis. Mol Cancer Ther 2006; 5: 522–32.

Kaur G, Belotti D, Burger AM, et al. Antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin: an orally bioavailable heat shock protein 90 modulator. Clin Cancer Res 2004; 10: 4813–21.

Agatsuma T, Ogawa H, Akasaka K, et al. Halohydrin and oxime derivatives of radicicol: synthesis and antitumor activities. Bioorg Med Chem 2002; 10: 3445–54.

Janin YL. Heat shock protein 90 inhibitors. A text book example of medicinal chemistry? J Med Chem 2005; 48: 7503–12.

Vilenchik M, Solit D, Basso A, et al. Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem Biol 2004; 11: 787–97.

Biamonte MA, Shi J, Hong K, et al. Orally active purine-based inhibitors of the heat shock protein 90. J Med Chem 2006; 49: 817–28.

Chiosis G, Lopes EC, Solit D. Heat shock protein 90 inhibitors: a chronicle from geldanamycin to today's agent. Curr Opin Invest Drugs 2006; 7: 534–41.

Cheung KM, Matthews TP, James K, et al. The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors. Bioorg Med Chem Lett 2005; 15: 3338–43.

Sharp SY, Rowlands M, Prodromou CS, et al. In vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of HSP90 inhibitors. Cancer Res 2007; 67: 2206–16.

Smith NF, Hayes A, James K, et al. Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors. Mol Cancer Ther 2006; 5: 1628–37.

Dymock BW, Barril X, Brough PA, et al. Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J Med Chem 2005; 48: 4212–5.

Sharp SY, Clarke PA, Powers M, et al. Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues. Mol Cancer Ther 2007; 6: 1198–211.

Brough PA, Aherne W, Barril X, et al. 4,5-Diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem 2008; 51: 196–218.

Howes R, Barril X, Dymock BW, et al. A fluorescence polarization assay for inhibitors of Hsp90. Anal Biochem 2006; 350: 202–13.

Roe SM, Prodromou C, O'Brien R, Ladbury JE, Piper PW, Pearl LH. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med Chem 1999; 42: 260–6.

Sharp SY, Kelland LR, Valenti MR, Brunton LA, Hobbs S, Workman P. Establishment of an isogenic human colon tumor model for NQO1 gene expression: application to investigate the role of DT-diaphorase in bioreductive drug activation in vitro and in vivo. Mol Pharmacol 2000; 58: 1146–55.

Cummings J, Zelcer N, Allen JD, et al. Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins. Biochem Pharmacol 2004; 67: 31–9.

Hostein I, Robertson D, DiStefano F, Workman P, Clarke PA. Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis. Cancer Res 2001; 61: 4003–9.

Zhang L, Fan J, Vu K, et al. 7′-Substituted benzothiazolothio- and pyridinothiazolothio-purines as potent heat shock protein 90 inhibitors. J Med Chem 2006; 49: 5352–62.

Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949–54.

Becker B, Multhoff G, Farkas B, et al. Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp Dermatol 2004; 13: 27–32.

Khaleque MA, Bharti A, Sawyer D, et al. Induction of heat shock proteins by heregulin β1 leads to protection from apoptosis and anchorage-independent growth. Oncogene 2005; 24: 6564–73.

Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N. Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res 2003; 63: 2139–44.

Sain N, Krishnan B, Ormerod MG, et al. Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT. Mol Cancer Ther 2006; 5: 1197–208.

Solit DB, Zheng FF, Drobnjak M, et al. 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 2002; 8: 986–93.

Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J Biol Chem 2002; 277: 29936–44.

Bardos JI, Ashcroft M. Hypoxia-inducible factor-1 and oncogenic signalling. Bioessays 2004; 26: 262–9.

Price JT, Quinn JM, Sims NA, et al. The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line. Cancer Res 2005; 65: 4929–38.

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Cancer Research

Tập 68 Số 8

2850-2860

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