Novel 3,4-isoxazolediamides as potent inhibitors of chaperone heat shock protein 90

Journal of Medicinal Chemistry

Volumn 54, Issue 24, 2011, Pages 8592-8604

  Baruchello, Riccardo ^a   Simoni, Daniele ^a   Grisolia, Giuseppina ^a   Barbato, Giuseppina ^a   Marchetti, Paolo ^a   Rondanin, Riccardo ^a   Mangiola, Stefania ^a   Giannini, Giuseppe ^a   Brunetti, Tiziana ^b   Alloatti, Domenico ^b   Gallo, Grazia ^b   Ciacci, Andrea ^b   Vesci, Loredana ^b   Castorina, Massimo ^b   Milazzo, Ferdinando M ^b   Cervoni, Maria L ^b   Guglielmi, Mario B ^b   Barbarino, Marcella ^b   Foderà, Rosanna ^b   Pisano, Claudio ^b   Cabri, Walter ^b   more..

^a UNIVERSITY OF FERRARA   (Italy)

^b Sigma Tau SpA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

3 [5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 3 ETHYLCARBAMOYLISOXAZOL 4 YLCARBAMOYL]CYCLOPENTANECARBOXYLIC ACID METHYL ESTER; 3,4 ISOXAZOLEDIAMIDE DERIVATIVE; 4 (CYCLOHEXANECARBONYLAMINO) 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL)ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 4 [(5 BROMOFURAN 2 CARBONYL)AMINO] 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL)ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 4 [(ADAMANTANE 1 CARBONYL)AMINO] 5 (5 CHLORO 2,4 DIHYDROXYPHENYL)ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 4 ACETYLAMINO 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL)ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 4 AMINO 5 [2,4 BIS(BENZYLOXY) 5 CHLOROPHENYL]ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 4 AMINO 5 [2,4 BIS(BENZYLOXY) 5 ISOPROPYLPHENYL]ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 4 (2,2 DIMETHYLPROPIONYLAMINO)ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 4 (4 METHOXYBENZOYLAMINO)ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 4 (4 MORPHOLIN 4 YLMETHYLBENZOYLAMINO)ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 4 (5 ETHYLISOXAZOLE 3 CARBONYL)AMINOISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 4 [(3 METHYLTHIOPHENE 2 CARBONYL)AMINO]ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 4 [(4 METHOXYCYCLOHEXANECARBONYL)AMINO]ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 4 [(FURAN 2 CARBONYL)AMINO]ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 (5 CHLORO 2,4 DIHYDROXYPHENYL) 4 (2,2 DIMETHYLPROPIONYLAMINO)ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 (5 CHLORO 2,4 DIHYDROXYPHENYL) 4 [(3 METHYLTHIOPHENE 2 CARBONYL)AMINO]ISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 [2,4 BIS(BENZYLOXY) 5 CHLOROPHENYL] 4 AMINO N (2,2,2 TRIFLUOROETHYL)ISOXAZOLE 3 CARBOXAMIDE; 5 [2,4 BIS(BENZYLOXY) 5 CHLOROPHENYL] 4 NITROISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; 5 [2,4 BIS(BENZYLOXY) 5 CHLOROPHENYL] N (2,2,2 TRIFLUOROETHYL) 4 NITROISOXAZOLE 3 CARBOXAMIDE; 5 [2,4 BIS(BENZYLOXY) 5 ISOPROPYLPHENYL] 4 NITROISOXAZOLE 3 CARBOXYLIC ACID ETHYLAMIDE; HEAT SHOCK PROTEIN 70; HEAT SHOCK PROTEIN 90 INHIBITOR; ISOXAZOLE DERIVATIVE; NITROGEN; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; BINDING AFFINITY; CANCER CELL CULTURE; CANCER INHIBITION; CONTROLLED STUDY; DRUG BINDING; DRUG POTENCY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PROTEIN DEPLETION; PROTEIN EXPRESSION; PROTEIN INDUCTION; SQUAMOUS CELL CARCINOMA;

AMIDES; ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CELL PROLIFERATION; CRYSTALLOGRAPHY, X-RAY; DRUG SCREENING ASSAYS, ANTITUMOR; FEMALE; HSP90 HEAT-SHOCK PROTEINS; HUMANS; ISOXAZOLES; MICE; MICE, NUDE; MODELS, MOLECULAR; NEOPLASM TRANSPLANTATION; PROTEIN CONFORMATION; RESORCINOLS; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSPLANTATION, HETEROLOGOUS;

EID: 84055221782     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm201155e     Document Type: Article

References (49)

1. Maloney, A.; Workman, P. Hsp90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin. Biol. Ther. 2002, 2, 3-24.
2. Whitesell, L.; Lindquist, S. L. Hsp90 and the chaperoning of cancer. Nat. Rev. Cancer 2005, 5, 761-772.
3. Kamal, A.; Boehm, M. F.; Burrows, F. J. Therapeutic and diagnostic implications of Hsp90 activation. Trends Mol. Med. 2004, 10, 283-290.
4. Pratt, W. B.; Morishima, Y.; Peng, H.-M.; Osawa, Y. Proposal for a role of the Hsp90/Hsp70-based chaperone machinery in making triage decisions when proteins undergo oxidative and toxic damage. Exp. Biol. Med. 2010, 235, 278-289.
5. Vega, V. L.; De Maio, A. Geldanamycin treatment ameliorates the response to LPS in murine macrophages by decreasing CD14 surface expression. Mol. Biol. Cell 2003, 14, 764-773.
6. Poulaki, V.; Iliaki, E.; Mitsiades, N.; Mitsiades, C. S.; Paulus, Y. N.; Bula, D. V.; Gragoudas, E. S.; Miller, J. W. Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis. FASEB J. 2007, 21, 2113-2123.
7. Kumar, R.; Pavithra, S. R.; Tatu, U. Three-dimensional structure of heat shock protein 90 from Plasmodium falciparum: molecular modelling approach to rational drug design against malaria. J. Biosci. 2007, 32, 531-536.
8. Solit, D. B.; Chiosis, G. Development and application of Hsp90 inhibitors. Drug Discovery Today 2008, 13c, 38-43.
9. Prodromou, C.; Peral, L. H. Structure and functional relationship of the Hsp90. Curr. Cancer Drug Targets 2003, 3, 301-323.
10. Cowena, L. E.; Singha, S. D.; Köhler, J. R.; Collins, C.; Zaas, A. K.; Schell, W. A.; Aziz, H.; Mylonakis, E.; Perfect, J. R.; Whitesellf, L.; Lindquistf, S. Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 2818-2823.
11. Connor, J. H.; McKenzie, M. O.; Parks, G. D.; Lyles, D. S. Antiviral activity and RNA polymerase degradation following Hsp90 inhibition in a range of negative strand viruses. Virology 2007, 362, 109-119.
12. Luo, W.; Dou, F.; Rodina, A.; Chip, S.; Kim, J.; Zhao, Q.; Moulick, K.; Aguirre, J.; Wu, N.; Greengard, P.; Chiosis, G. Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 9511-9516.
13. Zhang, H.; Burrows, F. Targeting multiple signal transduction pathways through inhibition of Hsp90. J. Mol. Med. 2004, 82, 488-499.
14. Workman, P. Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett. 2004, 206, 149-157.
15. Vilenchik, M.; Solit, D.; Basso, A.; Huezo, H.; Lucas, B.; He, H.; Rosen, N.; Spampinato, C.; Modrich, P.; Chiosis, G. Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem. Biol. 2004, 11, 787-797.
16. Csermely, P.; Schnaider, T.; Soti, C.; Prohaszka., Z.; Nardai, G. The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol. Ther. 1998, 79, 129-168.
17. Stravopodis, D. J.; Margaritis, L. H.; Voutsinas, G. E. Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. Curr. Med. Chem. 2007, 14, 3122-3138.
18. Whitesell, L.; Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 2005, 5, 761-772.
19. Picard, D. Heat-shock protein 90, a chaperone for folding and regulation. Cell. Mol. Life Sci. 2002, 59, 1640-1648.
20. Eustace, B. K.; Sakurai, T. A.; Stewart, J. K.; Yimlamai, D.; Unger, C.; Zehetmeier, C.; Lain, B.; Torella, C.; Henning, S. W.; Beste, G.; Scroggins, B. T.; Neckers, L.; Ilag, L. L.; Jay, D. G. Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat. Cell Biol. 2004, 6, 507-514.
21. Koga, F.; Tsutsumi, S.; Neckers, L. M. Low dose geldanamycin inhibits hepatocyte growth factor and hypoxia-stimulated invasion of cancer cells. Cell Cycle 2007, 6, 1393-1402.
22. Trepel, J.; Mollapour, M.; Giaccone, G.; Neckers, L. Targeting the dynamic HSP90 complex in cancer. Nat. Rev. Cancer 2010, 10, 537-549.
23. Whitesell, L.; Shifrin, S. D.; Schwab, G.; Neckers, L. M. Benzoquinonoid ansamycins possess selective tumoricidal activity unrelated to src kinase inhibition. Cancer Res. 1992, 52, 1721-1728.
24. Supko, J. G.; Hickman, R. L.; Grever, M. R.; Malspeis, L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother. Pharmacol. 1995, 36, 305-315.
25. Infinity Pharmaceuticals, Inc. Product Candidates. http://www.infi.com/ product-candidates-pipeline.asp.
26. Sharma, S. V.; Agatsuma, T.; Nakano, H. Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol. Oncogene 1998, 16, 2639-2645.
27. Biamonte, M. A.; Van de Water, R.; Arndt, J. W.; Scannevin, R. H.; Perret, D.; Lee, W.-C. Heat shock protein 90: inhibitors in clinical trials. J. Med. Chem. 2010, 53, 3-17.
28. Holzbeierlein, J. M.; Windsperger, A.; Vielhauer, G. Hsp90: a drug target? Curr. Oncol. Rep. 2010, 12, 95-101.
29. Taldone, T.; Chiosis, G. Purine-scaffold Hsp90 inhibitors. Curr. Top. Med. Chem. 2009, 9, 1436-1446.
30. He, H.; Zatorska, D.; Kim, J.; Aguirre, J.; Llauger, L.; She, Y.; Wu, N.; Immormino, R. M.; Gewirth, D. T.; Chiosis, G. Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90. J. Med. Chem. 2006, 49, 381-390.
31. Debiopharm Group. Pipeline. www.debiopharm.com/our-business/pipeline. html.
32. Huang, K. H.; Veal, J. M.; Fadden, R. P.; Rice, J. W.; Eaves, J.; Strachan, J.-P.; Barabasz, A. F.; Foley, B. E.; Barta, T. E.; Ma, W.; Silinski, M. A.; Hu, M.; Partridge, J. M.; Scott, A.; DuBois, L. G.; Freed, T.; Steed, P. M.; Ommen, A. J.; Smith, E. D.; Hughes, P. F.; Woodward, A. R.; Hanson, G. J.; McCall, W. S.; Markworth, C. J.; Hinkley, L.; Jenks, M.; Geng, L.; Lewis, M.; Otto, J.; Pronk, B.; Verleysen, K.; Hall, S. E. Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. J. Med. Chem. 2009, 52, 4288-4305.
33. Gopalsamy, A.; Shi, M.; Golas, J.; Vogan, E.; Jacob, J.; Johnson, M.; Lee, F.; Nilakantan, R.; Petersen, R.; Svenson, K.; Chopra, R.; Tam, M. S.; Wen, Y.; Ellingboe, J.; Arndt, K.; Boschelli, F. Discovery of benzisoxazoles as potent inhibitors of chaperone heat shock protein 90. J. Med. Chem. 2008, 51, 373-375.
34. Woodhead, A. J.; Angove, H.; Carr, M. G.; Chessari, G.; Congreve, M.; Coyle, J. E.; Cosme, J.; Graham, B.; Day, P. J.; Downham, R.; Fazal, L.; Feltell, R.; Figueroa, E.; Frederickson, M.; Lewis, J.; McMenamin, R.; Murray, C. W.; O'Brien, M. A.; Parra, L.; Patel, S.; Phillips, T.; Rees, D. C.; Rich, S.; Smith, D.-M.; Gary Trewartha, G.; Vinkovic, M.; Williams, B.; Woolford, A. J.-A. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1- ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J. Med. Chem. 2010, 53, 5956-5969.
35. Wang, Y.; Trepel, J. B.; Neckers, L. M.; Giaccone, G. STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr. Opin. Invest. Drugs 2010, 11, 1466-1476.
36. London, C. A.; Bear, M. D.; McCleese, J.; Foley, K. P.; Paalangara, R.; Inoue, T.; Ying, W.; Barsoum, J. Phase I Evaluation of STA-1474, a Pro-Drug of the Novel HSP90 Inhibitor Ganetespib, in Dogs with Spontaneous Cancer. Presented at the 102nd Annual Meeting of the AACR, Orlando, FL, Apr 2-6, 2011; Abstract 1282.
37. Papac, D. I.; Patton, J. S.; Reeves, L.; Bulka, K.; DeMie, L.; Roman, O.; Bradford, C.; Kim, S.-H.; Tangallapally, R.; Trovato, R.; Markovitz, B.; Bajji, A.; Wettstein, D.; Baichwal, V.; Mather, G. Comparative in Vitro and in Vivo Metabolism of MPC-3100, an Oral Hsp90 Inhibitor, in Rat, Dog, Monkey and Human. Presented at the 102nd Annual Meeting of the AACR, Orlando, FL, Apr 2-6, 2011; Abstract 3233.
38. Papac, D.; Patton, J. S.; Reeves, L.; DeMie, L.; Bradford, C.; Hachey, B.; Clemetson, B.; Christensen, C.; Kim, S.-H.; Tangallapally, R.; Parker, D.; Trovato, R.; Kim, I. C.; Wettstein, D.; Baichwal, V. R.; Bajji, A. Evaluation of the Pharmacokinetics and Efficacy of a Novel Pro-Drug of the Hsp90 Inhibitor, MPC-3100, Designed with Improved Solubility. Presented at the 102nd Annual Meeting of the AACR, Orlando, FL, Apr 2-6, 2011; Abstract 3237.
39. Cheung, K. M.; Matthews, T. P.; James, K.; Rowlands, M. G.; Boxall, K. J.; Sharp, S. Y.; Maloney, A.; Roe, S. M.; Prodromou, C.; Pearl, L. H.; Aherne, G. W.; McDonald, E.; Workman, P. 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, 3338-3343.
40. Brough, P. A.; Barril, X.; Beswick, M.; Dymock, B. W.; Drysdale, M. J.; Wright, L.; Grant, K.; Massey, A.; Surgenor, A.; Workman, P. 3-(5-Chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone. Bioorg. Med. Chem. Lett. 2005, 15, 5197-5201.
41. Brough, P. A.; Aherne, W.; Barril, X.; Borgognoni, J.; Boxall, K.; Cansfield, J. E.; Cheung, K. M.; Collins, I.; Davies, N. G.; Drysdale, M. J.; Dymock, B.; Eccles, S. A.; Finch, H.; Fink, A.; Hayes, A.; Howes, R.; Hubbard, R. E.; James, K.; Jordan, A. M.; Lockie, A.; Martins, V.; Massey, A.; Matthews, T. P.; McDonald, E.; Northfield, C. J.; Pearl, L. H.; Prodromou, C.; Ray, S.; Raynaud, F. I.; Roughley, S. D.; Sharp, S. Y.; Surgenor, A.; Walmsley, D. L.; Webb, P.; Wood, M.; Workman, P.; Wright, L. 4,5-Diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J. Med. Chem. 2008, 51, 196-218.
42. Dymock, B. W.; Barril, X.; Brough, P. A.; Cansfield, J. E.; Massey, A.; McDonald, E.; Hubbard, R. E.; Surgenor, A.; Roughley, S. D.; Webb, P.; Workman, P.; Wright, L.; Drysdale, M. J. Novel potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J. Med. Chem. 2005, 48, 4212-4215.
43. Smith, N. F.; Hayes, A.; James, K.; Nutley, B. P.; McDonald, E.; Henley, A.; Dymock, B.; Drysdale, M. J.; Raynaud, F. I.; Workman, P. Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors. Mol. Cancer Ther. 2006, 5, 1628-1638.
44. Brough, P. A.; Barril, X.; Borgognoni, J.; Chene, P.; Davies, N. G.; Davis, B.; Drysdale, M. J.; Dymock, B.; Eccles, S. A.; Garcia-Echeverria, C.; Fromont, C.; Hayes, A.; Hubbard, R. E.; Jordan, A. M.; Jensen, M. R.; Massey, A.; Merrett, A.; Padfield, A.; Parsons, R.; Radimerski, T.; Raynaud, F. I.; Robertson, A.; Roughley, S. D.; Schoepfer, J.; Simmonite, H.; Sharp, S. Y.; Surgenor, A.; Valenti, M.; Walls, S.; Webb, P.; Wood, M.; Workman, P.; Wright, L. Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J. Med. Chem. 2009, 52, 4794-4809.
45. Sharp, S. Y.; Boxall, K.; Rowlands, M.; Prodromou, C.; Roe, S. M.; Maloney, A.; Powers, M.; Clarke, P. A.; Box, G.; Sanderson, S.; Patterson, L.; Matthews, T. P.; Cheung, K. M.; Ball, K.; Hayes, A.; Raynaud, F.; Marais, R.; Pearl, L.; Eccles, S.; Aherne, W.; McDonald, E.; Workman, P. In vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of heat shock protein 90 inhibitors. Cancer Res. 2007, 67, 2206-2216.
46. Ohba, S.; Hirose, Y.; Yoshida, K.; Yazaki, T.; Kawase, T. Inhibition of 90-kD heat shock protein potentiates the cytotoxicity of chemotherapeutic agents in human glioma cells. J. Neurosurg. 2010, 112, 33-42.
47. Simoni, D.; Romagnoli, R.; Baruchello, R.; Rondanin, R.; Rizzi, M.; Pavani, M. G.; Alloatti, D.; Giannini, G.; Marcellini, M.; Riccioni, T.; Castorina, M.; Guglielmi, M. B.; Bucci, F.; Carminati, P.; Pisano, C. Novel combretastatin analogues endowed with antitumor activity. J. Med. Chem. 2006, 49, 3143-3152.
48. Giannini, G.; Cabri, W.; Simoni, D.; Baruchello, R.; Carminati, P.; Pisano, C. PCT Int. Appl. WO2010000748A1, 2010. Sigma-Tau Research Switzerland S.A. retains the property rights of all the compounds mentioned in the paper.
49. Kim, J.; Felts, S.; Llauger, L.; He, H.; Huezo, H.; Rosen, N.; Chiosis, G. Development of a fluorescence polarization assay for the molecular chaperone Hsp90. J. Biomol. Screening 2004, 9, 375-381.