Heat shock protein 90 inhibitors as therapeutic agents

Recent Patents on Anti-Cancer Drug Discovery

Volumn 7, Issue 3, 2012, Pages 313-336

  Gomez Monterrey, Isabel ^a   Sala, Marina ^b   Musella, Simona ^a   Campiglia, Pietro ^b  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^b UNIVERSITY OF SALERNO   (Italy)

Author keywords

Anticancer therapeutics; Development of antitumor agents; Drug discovery; Heat shock proteins (HSPs); Heat shock response; HSP90 inhibitors; HSP90 modulators; Molecular chaperones

Indexed keywords

5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 4 (4 MORPHOLINOMETHYLPHENYL) 3 ISOXAZOLECARBOXYLIC ACID ETHYLAMIDE; ADENOSINE TRIPHOSPHATE; ALVESPIMYCIN; ANSAMYCIN DERIVATIVE; AT 13387; BORTEZOMIB; CAPECITABINE; CETUXIMAB; CHAPERONE; CNF 1010; CNF 2024; DOCETAXEL; DS 2248; ERLOTINIB; GANETESPIB; GELDANAMYCIN; HEAT SHOCK PROTEIN 90; HEAT SHOCK PROTEIN 90 INHIBITOR; IMATINIB; IPI 493; KW 2478; MACBECIN; MPC 3100; PU H71; PURINE DERIVATIVE; RADICICOL; RETASPIMYCIN; SNX 5422; TANESPIMYCIN; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; XL 888;

ACUTE GRANULOCYTIC LEUKEMIA; AMINO TERMINAL SEQUENCE; BREAST METASTASIS; CARBOXY TERMINAL SEQUENCE; CARCINOGENESIS; CASTRATION RESISTANT PROSTATE CANCER; CELL COMPARTMENTALIZATION; CELL DIFFERENTIATION; CELL GROWTH; CELL SURVIVAL; CHOROID MELANOMA; CHRONIC MYELOID LEUKEMIA; COLORECTAL CANCER; DRUG RESEARCH; DRUG STRUCTURE; DRUG TARGETING; ESOPHAGUS CANCER; GASTROINTESTINAL STROMAL TUMOR; HUMAN; LIPOSARCOMA; LIVER TOXICITY; LUNG NON SMALL CELL CANCER; LUNG SMALL CELL CANCER; LYMPHOMA; MALIGNANT NEOPLASTIC DISEASE; MALIGNANT TRANSFORMATION; MULTIPLE MYELOMA; MYELODYSPLASTIC SYNDROME; MYELOPROLIFERATIVE DISORDER; NONHODGKIN LYMPHOMA; NONHUMAN; PANCREAS CANCER; PATENT; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN STABILITY; PROTEIN STRUCTURE; REVIEW; STOMACH CANCER;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DISCOVERY; DRUG SCREENING ASSAYS, ANTITUMOR; HSP90 HEAT-SHOCK PROTEINS; HUMANS; MODELS, BIOLOGICAL; NEOPLASMS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84867524294     PISSN: 15748928     EISSN: None     Source Type: Journal    
DOI: 10.2174/157489212801820066     Document Type: Review

References (232)

1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1): 57-70.
2. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
3. Kroemer G, Pouyssegur J. Tumor cell metabolism: Cancer's Achilles' heel. Cancer Cell 2008; 13(6): 472-82.
4. Teng MWL, Swann JB, Koebel CM, Schreiber RD, Smyth MJ. Immune-mediated dormancy: An equilibrium with cancer. J Leukoc Biol 2008; 84(4): 988-93.
5. Negrini S, Gorgoulis VS, Halazonetis TD. Genomic instability-an evolving hallmark of cancer Nature Rev Mol Cell Biol 2010; 11: 220-8.
6. Grivennikov SI, Greten FR, Karin M. Immunity, Inflammation, and Cancer. Cell 2010; 140(6): 883-99.
7. Sawyers C. Targeted cancer therapy. Nature 2004; 432: 294-7.
8. Weinstein IB, Joe A. Oncogene addiction. Cancer Res 2008; 68(9): 3077-80.
9. Strausberg RL, Simpson AJ, Old LJ, Riggins GJ. Oncogenomics and the development of new cancer therapies. Nature 2004; 429: 469-74.
10. Druker BJ. Inhibition of the Bcr-Abl tyrosine kinase as a therapeutic strategy for CML. Oncogene 2002; 21(56): 8541-6.
11. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogenactivated protein kinase cascade for the treatment of cancer. Oncogene 2007; 26(22): 3291-310.
12. Araujo RP, Liotta LA. A control theoretic paradigm for cell signaling networks: A simple complexity for a sensitive robustness. Curr Opin Chem Biol 2006; 10(1): 81-7.
13. Soo ETL, Yip GWC, Lwin ZM, Kumar SD, Bay B.-H. Heat shock proteins as novel targets in cancer. In vivo 2008; 22(3): 311-6.
14. Rajasethupathy P, Vayttaden SJ, Bhalla US. Systems modeling: A pathway to drug discovery. Curr Opin Chem Bio 2005; 9(4): 400-6.
15. Lamb J. The Connectivity Map: A new tool for biomedical research. Nat Rev Cancer 2007; 7(1): 54-60.
16. Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer 2005; 5(10): 761-72.
17. Workman P, Burrows F, Neckers L, Rosen, N. Drugging the cancer chaperone HSP90: Combinatorial therapeutic exploitation on oncogene addiction and tumor stress. Ann NY Acad Sci 2007; 1113: 202-16.
18. Kim YS, Alarcon SV, Lee S, Lee MJ, Giaccone G, Neckers L, et al. Update on HSP90 inhibitors in clinical trial. Curr Top Med Chem 2009; 9(15): 1479-92
19. Neckers L. Using natural product inhibitors to validate HSP90 as a molecular target in cancer. Curr Top Med Chem 2006; 6(11): 1163-71.
20. Amolins MW, Blagg BSJ. Natural product inhibitors of HSP90: potential leads for drug discovery. Mini Rev Med Chem 2009; 9(2): 140-52.
21. Taldone T, Gozman A, Maharaj R, Chiosis G. Targeting HSP90: Small-molecule inhibitors and their clinical development. Curr Opin Pharmacol 2008; 8(4): 370-4.
22. Biamonte MA, Van de Water R, Arndt JW, Scannevin RH, Perret D, Lee WC. Heat shock protein 90: Inhibitors in clinical trials. J Med Chem 2010; 53(1): 3-17.
23. Janin YL. ATPase inhibitors of heat-shock protein 90, second season. Drug Discov Today 2010; 15(9-10): 342-53.
24. Roughley SD, Hubbard RE. How well can fragments explore accessed chemical space? A case study from heat shock protein 90. J Med Chem 2011; 54(12): 3989-4005.
25. Gao Z, Garcia-Echeverria C, Jensen MR. HSP90 inhibitors: Clinical development and future opportunities in oncology therapy. Curr Opin Drug Discov Dev 2010; 13(2): 193-202.
26. Brandt GEL, Blagg BSJ. Alternate strategies of HSP90 modulation for the treatment of cancer and other diseases. Curr Top Med Chem 2009; 9(15): 1447-61.
27. McClellan AJ, Tam S, Kaganovich D, Frydman J. Protein quality control: Chaperones culling corrupt conformations. Nat Cell Biol 2005; 7(8): 736-41.
28. Ellis RJ. Protein misassembly: Macromolecular crowding and molecular chaperones. Adv Exp Med Biol 2007; 594: 1-13.
29. Freeman BC, Yamamoto KR. Disassembly of transcriptional regulatory complexes by molecular chaperones. Science 2002; 296(5576): 2232-5.
30. Young JC, Hoogenraad NJ, Hartl FU. Molecular chaperones HSP90 and HSP70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 2003; 112(1): 41-50.
31. Zhao R, Davey M, Hsu YC, Kaplanek P, Tong A, Parsons AB, et al. Navigating the chaperone network: An integrative map of physical and genetic interactions mediated by the HSP90 chaperone. Cell 2005; 120(5): 715-27.
32. Dutta R, Inouye M. GHKL, an emergent ATPase/kinase superfamily. Trends Biochem Sci 2000; 25(1): 24-8.
33. Pearl LH, Prodromou C. Structure and mechanism of the HSP90 molecular chaperone machinery. Ann Rev Biochem 2006; 75: 271-94.
34. Hawle P, Siepmann M, Harst A, Siderius M, Reusch HP, Obermann WM. The middle domain of HSP90 acts as a discriminator between different types of client proteins. Mol Cell Biol 2006; 26(22): 8385-95.
35. Hainzl O, Lapina MC, Buchner J, Richter K. The charged linker region is an important regulator of HSP90 function. J Biol Chem 2009; 284(34): 22559-67.
36. Dollins, DE, Warren JJ, Immormino RM, Gewirth DT. Structures of GRP94-nucleotide complexes reveal mechanistic differences between the HSP90 chaperones. Mol Cell 2007; 28(1): 41-56.
37. Felts SJ, Owen BA, Nguyen P, Trepel J, Donner DB, Toft DO. The HSP90-related protein TRAP-1 is a mitochondrial protein with distinct functional properties. J Biol Chem 2000; 275(5): 3305-12.
38. Wandinger SK, Richter K, Buchner J. The HSP90 chaperone machinery. J Biol Chem 2008; 283(27): 18473-7.
39. Pearl LH, Prodromou C, Workman P. The HSP90 molecular chaperone: An open and shut case for treatment. Biochem J 2008; 410(3): 439-53.
40. Taipale M, Jarosz DF, Lindquist S. HSP90 at the hub of protein homeostasis: Emerging mechanistic insights. Nat Rev Mol Cell Biol 2010; 11(7): 515-28.
41. Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 2010; 10(8): 537-49.
42. Bagatell R, Whitesell L. Altered HSP90 function in cancer: A unique therapeutic opportunity. Mol Cancer Ther 2004; 3(8): 1021-9.
43. Rutherford SL, Lindquist S. HSP90 as a capacitor for morphological evolution. Nature 1998; 396(6709): 336-42.
44. Wong KSH, Houry WA. Hsp90 at the crossroads of genetics and epigenetics. Cell Research 2006; 16: 742-9.
45. Goldstein MG, Li Z. Heat-shock proteins in infection-mediated inflammation-induced tumorigenesis. J Hematol Oncol 2009; 2: 5-10.
46. Mittelman D, Sykoudis K, Hersh M, Lin Y, Wilson JH. HSP90 modulates CAG repeat instability in human cells. Cell Stress-Chaperones 2010; 15(5): 753-9.
47. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Parsons AB, et al. A high-affinity conformation of HSP90 confers tumor selectivity on HSP90 inhibitors. Nature 2003; 425(6956): 407-10.
48. DeBoer C, Meulman PA, Wnuk RJ, Peterson DH. Geldanamycin, a new antibiotic. J Antibiot 1970; 23(9): 42-7.
49. De Boer, C., Peterson, D.H. Antibiotic Geldanamycin. US3595955 (1971).
50. Whitesell, L., Neckers, L., Trepel, J., Myers, C. Tumoricidal activity of benzoquinonoid ansamycins against prostate cancer and primitive neural malignancies. WO9408578 (1994).
51. Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP. Crystal structure of an HSP90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent. Cell 1997; 89(2): 239-50.
52. Tian, Z. Q, McDaniel, R., Myles, D.C., Patel, K.G., Piagentini, M., Wang, Z. 2-Desmethyl ansamycin compounds. US7241754 (2007).
53. Santi, D.V., Tian, Z.Q., Liu, Y., Wang, Z. Geldanamycin compounds and method of use. US7378407 (2008).
54. Erlichman C. Tanespimycin: The opportunities and challenges of targeting heat shock protein 90. Expert Opin Investig Drugs 2009; 18(6): 861-8.
55. Usmani SZ, Robert B, Zihai L. 17 AAG for HSP90 inhibition in cancer-from bench to bedside. Curr Mol Med 2009, 9(5): 654-64.
56. Samuni Y, Ishii H, Hyodo F, Samuni U, Krishna MC, Goldstein S, Mitchell JB. Reactive oxygen species mediate hepatotoxicity induced by the Hsp90 inhibiting anti-cancer geldanamycin and its analogs. Free Radic Biol Med 2010; 48(11): 1559-63.
57. Powers MV, Workman P. Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 2007; 581(19): 3758-69.
58. Dams, J., Gao, Y., Evangelinos G.A.T., Grenier, L., Pak, R.H., Porter, J.R. Wright, J.L. Analogs of benzoquinone-containing ansamycins for the treatment of cancer, WO2005063714 (2005).
59. Sydor JR, Normant E, Pien CS, Porter JR, Ge J, Grenier L, et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against HSP90. Proc Natl Acad Sci USA 2006; 103(46): 17408-13.
60. Erlichman C. Tanespimycin: The opportunities and challenges of targeting heat shock protein 90. Expert Opin Investig Drugs 2009; 18(6): 861-8.
61. thEORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Brussels, Belgium, October 20-24, 2008.
62. Rascher A, Hu Z, Buchanan GO, Reid R, Hutchinson CR. Insights into the biosynthesis of the benzoquinone ansamycins geldanamycin and herbimycin, obtained by gene sequencing and disruption. Appl Enviro Microbiol 2005; 71(8): 4862-71.
63. Menzella HG, Tran T-T, Carney JR, Lau-Wee J, Galazzo J, Reeves CD, et al. Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus. J Med Chem 2009; 52(6): 1518-21.
64. Guiblin, A.R., Wilkinson, B., Moss, S.J., Zhang, M.-Q., McElhinney, A.D., Martin, C.J. Ansamycin derivatives for the treatment of cancer or B-cell malignancies. WO2007026027 (2007).
65. Zhang MQ, Gaisser S, Nur-E-Alam M, Sheehan LS, Vousden WA, Gaitatzis N, et al. Optimizing natural products by biosynthetic engineering: Discovery of nonquinone HSP90 inhibitors. J Med Chem 2008; 51(18): 5494-7.
66. Chiosis G, Timaul MN, Lucas B, Munster PN, Zheng FF, Sepp-Lorenzino L, et al. A small molecule designed to bind to the adenine nucleotide pocket of HSP90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells Chem Biol 2001; 8(3): 289-99.
67. Kasibhatla, S.R., Hong, K., Zhang, L., Biamonte, M.A., Boehm, M.F., Shi, J., Fan, J. Preparation of purine analogs as heat shock protein 90 (HSP90) inhibitors. WO03037860 (2003).
68. Biamonte MA, Shi J, Hong K, Hurst DC, Zhang L, Fan J, et al. Orally active purine-based inhibitors of the heat shock protein 90. J Med Chem 2006; 49(2): 817-28.
69. He H, Zatorsk D, Kim J, Aguirre J, Llauger L, She Y, et al. Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90. J Med Chem 2006; 49(1): 381-90.
70. Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, et al. HSP90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci USA 2009; 106(20): 8368-73.
71. Cai, X., Qian, C., Zhai, H. Fused amino pyridine as HSP90 inhibitors. WO2008115719 (2008).
72. Bao R, Lai CJ, Qu H, Wang D, Yin L, Zifcak B, et al. CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res 2009; 15(12): 4046-57.
73. Bajji, A.C., Kim, S.-H., Markovitz, B., Trovato, R., Tangallapally, R., Anderson, M.B., Wettstein, D., Shenderovich, M., Vanecko, J.A. Therapeutic compounds and their use in cancer. WO2007134298 (2007).
74. Bajji, A.C. Kim, S.-H., Tangallapally, R., Markovitz, B., Trovato, R., Anderson, M.B., Wettstein, D., Shenderovich, M. Therapeutic compounds and their use in treating diseases and disorders. WO2009065035 (2009).
75. Samlowski WE, Papadopoulos K, Olszanski AJ, Cimbora D, Baichwal V, Shawbell S, et al. Phase 1 study of the HSP90 inhibitor MPC-3100 in subjects with refractory or recurrent cancer. AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics, San Francisco, CA, USA November 12-16, 2011
76. Moffat, D.C.F., Baker, K.W.J., Donald, A.D.G., Day, F.A. Purine derivatives suitable for the treatment of cancer, autoimmune and inflammatory diseases. WO2009136144 (2009).
77. Qian, C., Cai, X., Gould, S., Zhai, H. Preparation of benzodioxolyl purine derivatives as HSP90 inhibitors containing a zinc binding moiety. WO2008115262 (2008).
78. Kasibhatla, S.R., Biamonte, M.A., Shi, J., Boehm, M.F. Alkynylpyrrolo[2,3-d]pyrimidines as HSP90 inhibitors, their preparation, Pharmaceuticals compositions, and use in therapy. WO2006105372 (2006).
79. Kasibhatla SR, Hong K, Biamonte MA, Busch DJ, Karjian PL, Sensintaffar JL, et al. Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity. J Med Chem 2007; 5(12): 2767-78.
80. Lundgren K, Zhang H, Brekken J, Huser N, Powell RE, Timple N, et al. BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein HSP90. Mol Cancer Ther 2009; 8(4): 921-9.
81. Kasibhatla, S.R., Biamonte, M.A., Shi, J., Boehm, M.F. Alkynylpyrrolo[2,3-d] pyrimidines as HSP90 inhibitors, their preparation, Pharmaceuticals compositions, and use in therapy. WO2006105372 (2006).
82. Yun TJ, Harning EK, Giza K, Rabah D, Li P, Arndt JW, et al. EC144, a synthetic inhibitor of heat shock protein 90, blocks innate and adaptive immune responses in models of inflammation and autoimmunity. J Immunol 2011; 186(1): 563-75.
83. Day, F.A., Launay, D.F.M., Charlton, M.H., Moffat, D.F.C. HSP90 inhibitors. WO2010043865 (2010) & WO2010043867 (2010).
84. Ohsuki, S., Tengeiji, A., Ikeda, M., Shibata, Y., Nagata, C., Shimada, T. Pyrazolopyrimidine derivative. WO2008035629 (2008).
85. Sun, C.L., Li, X., Zhu, Y. Bioactive compounds for treatment of cancer and neurodegenerative diseases. WO2009139834 (2009).
86. Brough, P.A., Barril-Alonso, X., Drysdale, M.J. Pyrimidothiophene compounds for use as HSP90 inhibitors. WO2006090094 (2006).
87. Brough PA, Barril X, Borgognoni J, Chene P, Davies NG, Davis B, et al. 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(15): 4794-809.
88. Kung, P.P., Meng, J.J. Preparation of 2-aminopyrimidine derivatives as HSP90 inhibitors. WO2008059368 (2008).
89. Zehnder L, Bennet M, Meng J, Huang B, Ninkovic S, Wang F, et al. Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-Amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide. J Med Chem 2011; 54(9): 3368-85.
90. Machajewski, T.D., Gao, Z., Levine, B.H., Antonios-McCrea, W., Bellamacina, C.R., Costales, A., Doughan, B.M., Fong, S., Hendrickson, T., Lin, X., Mcbride, C., McKenna, M., Rico, A.C., Shafer, C.M., Wang, X.M., Zhou, Y., Xia, Y., Mendenhall, K.G. 2-Amino-quinazolin-5-ones as HSP90 inhibitors useful in treating proliferation diseases. WO2006113498 (2006).
91. Machajewski, T.D., Shafer, C.M., McBride, C., Antonios-McCrea, W., Doughan, B. M., Levine, B.H., Xia, Y., Mckenna, M., Wang, X.M., Mendenhall, K., Zhou, Y., Gong, B., Gu, D., Dolan, J., Tulinsky, J., Brinner, K., Gao, Z. 2-Amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-ones WO2007041362 (2007).
92. Courtney, S.M., Whittaker, M., Mather, O.C., Yarnold, C.J., Barker, O.R., Montalbetti, C.A.G.N., Hesterkamp, T., Gardiner, M.D. Quinazolin-oxime derivatives as HSP90 inhibitors. WO2008142720 (2008).
93. Stafford, J.A., Guntupalli, P., Notz W.R.L., Ton-Nu, H.-T., Co, E.W., Chen, Y.K., Lawson, J.D. Oxime derivatives as HSP90 inhibitors. WO2009097578 (2009).
94. Huang, K.H., Eaves, J., Veal, J. M., Barta, T., Geng, L., Hinkley, L., Hanson, G. Tetrahydroindolone and tetrahydroindazolone derivatives. WO2006091963 (2006).
95. Barta TE, Veal JM, Rice JW, Partridge JM, Fadden RP, Ma W, et al. Discovery of benzamide tetrahydro-4H-carbazol-4-ones as novel small molecule inhibitors of HSP90. Bioor Med Chem Lett 2008; 18(12): 3517-21.
96. Huang, K.H., Hughes, P., Ma, W., Ommen, A., Woodward, A., Veal, J., Barta, T. Tetrahydroindolone and tetrahydroindazolone derivatives. WO2008024970 (2008).
97. Huang KH, Veal JM, Fadden RP, Rice JW, Eaves J, Strachan JP, et al. Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. J Med Chem 2009; 52(14): 4288-305.
98. Chandarlapaty S, Sawai A, Ye Q, Scott A, Silinski M, Huang K, et al. SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin Cancer Res 2008; 14(1): 240-8.
99. Okawa Y, Hideshima T, Steed P, Vallet S, Hall S, Huang K, et al. SNX-2112, a selective HSP90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumor by abrogating signaling via Akt and ERK. Blood 2009; 113(4): 846-55.
100. Rice JW, Veal JM, Fadden RP, Barabasz AF, Partridge JM, et al. SNX-7081, Small molecule inhibitors of HSP90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis. Arthritis Rheum 2008; 58(12): 3765-75.
101. Best OG, Singh N, Forsyth C, Mulligan SP. The novel Hsp-90 inhibitor SNX7081 is significantly more potent than 17-AAG against primary CLL cells and a range of haematological cell lines, irrespective of lesions in the TP53 pathway. Br J Haematol 2010; 151(2): 185-8.
102. Denissova, I., Fournie, J.H., Jaquit, J.B., Laurent, A., Rose, Y., Proulx, M. HSP90 modulating compounds, composition, methods and uses. WO2011035416 (2011).
103. Martinell, P.M., Navarro, M.I., Soler, L.M., Mormeneo, J.D., Rosol, M., Llebaria, S.A. New compounds as HSP90 inhibitors. WO2009007399 (2009).
104. Winssinger N, Fontaine JG, Barluenga S. HSP90 inhibition with resorcyclic acid lactones (rals). Curr Top Med Chem 2009; 9(15): 1419-35.
105. Proisy N, Sharp SY, Boxall K, Connelly S, Roe SM, Prodromou C, et al. Inhibition of HSP90 with synthetic macrolactones: Synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. Chem Biol 2006, 13(11): 1203-15
106. Soga S, Shiotsu Y, Akinaga S, Sharma SV. Development of radicicol analogs. Curr Cancer Drug Targets 2003, 3(5): 359-69.
107. Wissinger, N., Barluenga, S., Karplus, M. Synthesis of resocylic lactones useful as therapeutic agents. WO2009091921 (2009).
108. Barluenga S, Fontaine JG, Wang C, Aouadi K, Chen R, Beebe K, et al. Inhibition of HSP90 with pochoximes: SAR and structurebased insights. Chembiochem 2009; 10(17): 2753-9.
109. Zhu H, Woolfenden S, Bronson RT, Jaffer AM, Barluenga S, Winssinger N, et al. The novel HSP90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme. Mol Cancer Ther 2010; 9(9): 2618-26
110. Cheung KM, Matthews TP, James K, Rowlands MG, Boxall KJ, Sharp SY, 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(14): 3338-43
111. Kreusch A, Han S, Brinker A, Zhou V, Choi HS, He Y, et al. Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles. Bioorg Med Chem Lett 2005; 15(5): 1475-8.
112. Sharp SY, Boxall K, Rowlands M, Prodromou C, Roe SM, Maloney A, et al. In vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of heat shock protein 90 inhibitors. Cancer Res 2007; 67(5): 2206-16.
113. Sharp SY, Prodromou C, Boxall K, Powers MV, Holmes JL, Box G, et al. Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogs Mol Cancer Ther 2007; 6(4): 1198-211.
114. Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, et al. 4,5-diarylisoxazole HSP90 chaperone inhibitors: Potential therapeutic agents for the treatment of cancer. J Med Chem 2008; 51(2): 196-218.
115. Eccles SA, Massey A, Raynaud FI, Sharp SY, Box G, Valenti M, et al. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis Cancer Res 2008; 68(8): 2850-60.
116. Giannini, G., Cabri, W., Simoni, D., Barucchello, R., Carminati, P., Pisano, C. New 5-phenyl-isoxazole-3-carboxamides with antitumoral activities. WO2010000748 (2010).
117. Baruchello R, Simoni D, Grisolia G, Barbato G, Marchetti P, Rondanin R, et al. Novel 3,4-isoxazolediamides as potent inhibitors of chaperone heat shock protein 90. J Med Chem dx. doi.org/10.1021/jm201155e.
118. Eggenweiler, H.-M., Wolf, M. Triazole derivatives. WO2006087077 (2006).
119. Eggenweiler, H.-M., Wolf, M., Buchstaller, H.-P., Sirrenberg, C. Triazole derivatives as an HSP90 inhibitor. WO2008086857 (2008).
120. Ying, W., Przewloka, T., Chae, J.Z., Shijie, L. H., Du, Z., James, D., Chimmanamada, D.U., Ng, H.P., Foley, K., Demko, Z., Sun, L., Zhou, D., Qin, S. Triazole compounds that modulate HSP90 activity. WO2007139967 (2007).
121. Ying, W., Foley, K. Triazole derivatives as HSP90 modulators. WO2008021364 (2008).
122. Chimmanamada, D.U., Burlison, J.A., Ying, W., Sun, L., Schweizer, S.M., Zhang, S., Demko, Z., James, D., Przewloka, T. Triazole compounds that are useful in the treatment of proliferative disorders, such as cancer. WO2008097640 (2008).
123. Ying, W., Sun, L., Koya, K., Chimmanamada, D.U., Zhang, S., Przewloka, T., Li, H. Triazole compounds that modulate HSP90 activity. WO2009023211 (2009).
124. Lin TY, Bear M, Du Z, Foley KP, Ying W, Barsoum J, London C. The novel HSP90 inhibitor STA-9090 exhibits activity against Kitdependent and-independent malignant mast cell tumor. Exp Hematol 2008; 36(10): 1266-77.
125. McCleese JK, Bear MD, Fossey SL, Mihalek RM, Foley KP, Ying W, et al. The novel HSP90 inhibitor STA-1474 exhibits biologic activity against osteosarcoma cell lines. Int J Cancer 2009; 125(12): 2792-801.
126. Wang Y, Trepel JB, Neckers LM, Giaccone G. STA-9090, a smallmolecule HSP90 inhibitor for the potential treatment of cancer. Curr Opin Invest Drugs 2010; 11(12): 1466-76.
127. Feldman RI, Mintzer B, Zhu D, Wu JM, Biroc SL, Yuan S, et al. Potent triazolothione inhibitor of heat-shock protein-90. Chem Biol Drug Des 2009; 74(1): 43-50.
128. Burlison, J.A., Chimmanamada, D.U., Ying, W., Zhang, S., James, D. Hydrazonamide compounds that modulate HSP90 activity. WO2009158026 (2009).
129. Chimmanamada, D.U., Ying, W. Pyrrole compounds that modulate HSP90 activity WO2009148599 (2009).
130. Yang, R.-Y., Ali, S.M., Ashwell, M.A., Kelleher, E., Palma, R., Westlund, N. Substituted tetrazoles compounds and uses thereof. WO2009049305 (2009).
131. Matulis, D., Cikotiene, I., Kazlauskas, E., Matuliene, J. 5-Aryl-4-(5-substituted 2,4-dihydroxyphenyl)-1,2,3-thiadiazoles as inhibitors of HSP90 chaperone and the intermediates for production thereof. W02009134110 (2009).
132. Norrild, J.C., Lauritsen, A., Björkling, F., Vadlamudi, S.M. Preparation of 4-substituted-6-isopropylbenzene-1,3-diol compounds and their use. WO2009066060 (2009).
133. Kanda, Y., Soga, S., Nakashima, T., Nara, S., Nakagawa, H., Shiotsu, Y. Anti-tumor agent. WO2006088193 (2006).
134. Cavenagh JD, Yong K, Byrne J, Cavet J, Johnson P, Morgan G, et al. The safety, pharmacokinetics and pharmacodynamics of KW-2478, a novel HSP90 antagonist, in patients with B-cell malignancies: A firstling-man, phase I, multicentre, open-label, dose escalation study. American Society of Hematology-50th annual meeting and Exposition, San Francisco, USA (2011).
135. Nakashima T, Ishii T, Tagaya H, Seike T, Nakagawa H, Kanda Y, et al. New molecular and biological mechanism of antitumor activities of KW-2478, a novel nonansamycin heat shock protein 90 inhibitor, in multiple myeloma cells. Clin Cancer Res 2010; 16(10): 2792-802.
136. Frederickson, M., Lyons, J.F., Thompson, N.T., Vinkovic, M., Williams, B., Woodhead, A.J., Woolford, A.J. A. Hydrobenzamide derivatives as inhibitors of HSP90. WO2008044034 (2008).
137. Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, et al. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroiso indol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone HSP90 by fragment based drug design. J Med Chem 2010; 53(16): 5956-69.
138. Cho-Schultz, S., Huang, B., Kung, P.-P., Sutton, S.C. Amide resorcinol compounds. WO2008053319 (2008).
139. Kung PP, Huang B, Zhang G, Zhou JZ, Wang J, Digits JA, et al. Dihydroxyphenyl-isoindoline amides as orally bioavailable inhibitors of the heat shock protein 90 (HSP90) molecular chaperone. J Med Chem 2010; 53(1): 499-503.
140. Eggenweiler, H.-M., Sirrenberg, C., Buchstaller, H.-P. 1-3-Dihydroisoindole derivatives. WO2009030316 (2009).
141. Buchstaller, H.P., Eggenweiler, H.M., Wolf, M., Sirrenberg, C. Indazole derivatives for treating Hsp-90-induced diseases. WO2008003396 (2008).
142. Buchstaller, H.-P., Eggenweiler, H.-M., Sirrenberg, C. Indazolamide derivatives. WO2008155001 (2008).
143. Barril X, Brough P, Drysdale M, Hubbard RE, Massey A, Surgenor A, et al. Structure-based discovery of a new class of HSP90 inhibitors. Bioorg Med Chem Lett 2005; 15(23): 5187-91.
144. Ganesh T, Thepchatri P, Li L, Du Y. Fu H, Snyder JP, Sun A. Synthesis and SAR study of N-(4-hydroxy-3-(2-hydroxynaphthalene-1-yl)phenyl)-arylsulfonamides: Heat shock protein 90 (HSP90) inhibitors with submicromolar activity in an in vitro assay. Bioorg Med Chem Lett 2008; 18(18): 4982-7.
145. Rice, K.D., Aay, N., Anand, N.K., Arcalas, A., Baik, T.-G., Blazey, C.M., Bowles, O. J., Buhr, C.A., Bussenius, J., Costanzo, S., Curtis, J.K., Defina, S.C., Dubenko, L., Kennedy, A.R., Kim, A.I., Lara, K., Ma, S., Manalo, J.-C.L., Peto, C.J., Tsang, T.H., Wang, L. Tropane compounds. WO2009055077 (2009).
146. thEORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Brussels, Belgium, October 20-24, 2008
147. Mailliet P, Minoux H, Lyman SK, Crawley SC, Gong R, Adamkewicz JI, et al. High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888. PLoS ONE 2011; 6(3): e17692.
148. Alasia, M., Bertin, L., Certal, V., Halley, F., Mailliet, P., Mendez, P.M., Minoux, H., Ruxer, J.-M. Novel HSP90 inhibitory carbazole derivatives, compositions containing same, and use thereof. WO2009122034 (2009).
149. Ruxer, J.M., Certal, V., Alasia, M., Bertin, L., Minoux, H., Mailliet, P., Halley, F., Mendez-perez, M. Novel HSP90 inhibitory carbazole derivatives, compositions containing same and use thereof. US20110166169 (2011).
150. Vallee F, Carrez C, Pilorge F, Dupuy A, Parent A, Bertin L, et al. Tricyclic series of heat shock protein 90 (HSP90) inhibitors part I: Discovery of tricyclic imidazo[4,5-c]pyridines as potent inhibitors of the HSP90 molecular chaperone. J Med Chem 2011; 54(20): 7206-19.
151. Ganesh T, Min J, Thepchatri P, Du Y. Li L, Lewis I, et al. Discovery of aminoquinolines as a new class of potent inhibitors of heat shock protein 90 (HSP90): Synthesis, biology, and molecular modeling. Bioorg Med Chem 2008; 16 (14): 6903-10.
152. Sun, A., Ganesh, T., Min, J., Thepchatri, P., Du, Y. Aminoquinoline derived Heat Shock Protein 90 inhibitors, methods of preparing same, and methods for their use. WO2010042489 (2010).
153. Min J., Du, Y., Thepchatri, P., Liotta, D.C. Fu, H. Heat shock protein 90 inhibitors, methods of preparing same, and methods for their use. WO2010042500 (2010).
154. Oh SH, Woo JK, Yazici YD, Myers JN, Kim WY, Jin Q, et al. Structural basis for depletion of Heat Shock Protein 90 client proteins by deguelin. Natl Cancer Inst 2007; 99 (12): 949-61.
155. Kim W-Y, Chang DJ, Hennessy B, Kang HJ, Yoo J, Han S-H, et al. A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy. Cancer Prev Res 2008; 1(7): 577-87.
156. Bagatell R, Paine-Murrieta GD, Taylor CW, Pulcini EJ, Akinaga S, Benjamin IJ, et al. Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of HSP90-binding agents. Clin Cancer Res 2000; 6: 3312-8.
157. Donnelly A, Blagg BSJ. Novobiocin and additional inhibitors of the HSP90 C-terminal nucleotide-binding pocket. Curr Med Chem 2008; 15(26): 2702-17.
158. Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C. Intracellular and extracellular functions of heat shock proteins: Repercussions in cancer therapy. J Leukoc Bio 2007; 81(1): 15-27.
159. McLaughli M, Vandenbroeck K. The endoplasmic reticulum protein folding factory and its chaperones: New targets for drug discovery? Br J Pharm 2011; 162(2): 328-45.
160. Kang BH, Plescia J, Dohi T. Rosa J, Doxsey SJ, Altieri DC. Regulation of tumor cell mitochondrial homeostasis by an organellespecific HSP90 chaperone network. Cell 2007; 131(2): 257-70.
161. Nichols RL, Finland M. Novobiocin, a limited bacteriologic and clinical study of its use in fortyfive patients. Antibiotic Med Clin Ther 1956; 2(4): 241-57.
162. Marcu MG, Chadli A, Bouhouche I, Catelli M, Neckers LM. The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J Biol Chem 2000; 275(47): 37181-6.
163. Allan RK, Mok D, Ward BK, Ratajczak T. Modulation of chaperone function and cochaperone interaction by novobiocin in the Cterminal domain of HSP90: Evidence that coumarin antibiotics disrupt HSP90 dimerization. J Biol Chem 2006; 281(11): 7161-71.
164. Burlison JA, Neckers L, Smith AB, Maxwell A, Blagg BSJ. Novobiocin: Redesigning a DNA gyrase inhibitor for selective inhibition of HSP90. J Am Chem Soc 2006; 128(48): 15529-36.
165. Blagg, B.S., Neckers, L., Yu, X.M. Novobiocin analogs as anticancer agents. WO2006050501 (2006).
166. Blagg, B.S. Novobiocin analogs. US20090187014 (2009).
167. Burlison JA, Avila C, Vielhauer G, Lubbers DJ, Holzbeierlein J, Blagg BSJ. Development of novobiocin analogs that manifest antiproliferative activity against several cancer cell lines. J Org Chem 2008; 73(6): 2130-7.
168. Blagg, B.S., Zhao, H., Donnelly, A.C. Novobiovcin analogs having modified sugar moieties. WO2010096650 (2010).
169. Shelton SN, Shawgo ME, Matthews SB, Lu Y, Donnelly AC, Szabla K, et al. KU135, a novel novobiocin-derived C-terminal inhibitor of the 90-kda heat shock protein, exerts potent antiproliferative effects in human leukemic cells. Mol Pharmacol 2009; 76(6): 1314-22.
170. Samadi AK, Zhang X, Mukerji R, Donnelly AC, Blagg BS, Cohen MS. A novel C-terminal HSP90 inhibitor KU135 induces apoptosis and cell cycle arrest in melanoma cells. Cancer Lett 2011; 312(2): 158-67.
171. Kusuma BR, Peterson LB, Zhao H, Vielhauer G, Holzbeierlein J, Blagg BSJ. Targeting the heat shock protein 90 dimer with dimeric inhibitors. J Med Chem 2011; 54(18): 6234-53.
172. Le Bras G, Radanyi C, Peyrat JF, Brion JD, Alami M, Marsaud V, et al. New novobiocin analogs as antiproliferative agents in breast cancer cells and potential inhibitors of heat shock protein 90. J Med Chem 2007; 50(24): 6189-200.
173. Radanyi C, Le Bras G, Messaoudi S, Bouclier C, Peyrat JF, Brion JD, et al. Synthesis and biological activity of simplified denoviosecoumarins related to novobiocin as potent inhibitors of heat-shock protein 90 (HSP90). Bioorg Med Chem Lett 2008; 18(7): 2495-8.
174. Radanyi C, Le Bras G, Bouclier C, Messaoudi S, Peyrat JF, Brion JD, et al. Tosylcyclonovobiocin acids promote cleavage of the HSP90-associated cochaperone p23. Biochem Biophys Res Commun 2009; 379(2): 514-8.
175. Ni M, Lee AS. ER chaperones in mammalian development and human diseases. FEBS Lett. 2007; 581(19): 3641-51.
176. Nicchitta CV, Carrick DM, Baker-Lepain, JC. The messenger and the message: gp96 (GRP94)-peptide interactions in cellular immunity. Cell Stress Chaperones 2004; 9(4): 325-31.
177. Srivastava PK. Therapeutic cancer vaccines. Curr Opin Immunol 2006; 18(2): 201-5.
178. Podack ER, Raez LE. Allogeneic tumor-cell-based vaccines secreting endoplasmic reticulum chaperone gp96. Exp Opin Biol Ther 2007; 7(11): 1679-88.
179. Parsa C, Crane S, Han V, Kivett A, Fedoroff NA, Butowski, SM, et al. Autologous heat shock protein vaccine (HSPPC-96) for patients with recurrent glioblastoma (GBM): Results of a phase II multicenter clinical trial with immunological assessments. J Clin Oncol 2011; 29: (suppl, abstr 2565)
180. Eton O, Ross MI, East MJ, Mansfield PF, Papadopoulos N, Ellerhorst JA, et al. Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma. J Transl Med 2010; 8: 9
181. Pacey S, Banerj U, Judson I, Workman P. HSP90 Inhibitors in the Clinic. Handb Exp Pharmacol 2006; 172: 331-58.
182. Gewirth, D.T., Nicchitta, C.V. Isolated GRP94 ligand binding domain polypeptide and nucleic acid encoding same, crystalline form of same, and screening method employing same. US7991601 (2010).
183. Finotti, P. Complexes of grp94 with human immunoglobulin g. WO2009013097 (2009).
184. Im CN, Lee J S, Zheng Y, Seo JS. Iron chelation study in a normal human hepatocyte cell line suggests that tumor necrosis factor receptor-associated protein 1 (TRAP-1) regulates production of reactive oxygen species. J Cell Biochem 2007; 100(2): 474-86.
185. Pridgeon JW, Olzmann JA, Chin LS, Li L. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP-1. PLoS Biol 2007; 5:e172
186. Leav I, Plescia J, Goel HL, Li J, Jiang Z, Cohen RJ, et al. Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. Am J Pathol 2009; 176(1): 393-401.
187. Altieri, D.C., Kang, B.H. Mitocondria-targeted anti-tumor agents. WO2009036092 (2009).
188. Kang BH, Plescia J, Song HY, Meli M, Colombo G, Beebe K, et al. Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial HSP90. J Clin Invest 2009; 119(3): 454-64.
189. Kang BH, Siegelin MD, Plescia J, Raskett CM, Garlick DS, Dohi T, et al. Preclinical characterization of mitochondria-targeted small molecule HSP90 inhibitors, Gamitrinibs, in advanced prostate. Cancer Clin Cancer Res 2010; 16(19): 4779-88.
190. Ullrich SJ, Robinson EA, Law LW, Willingham M, Appella E. A mouse tumor-specific transplantation antigen is a heat shock related protein. Proc Natl Acad Sci USA 1986; 83(10): 3121-25.
191. Basu S, Srivastava PK. Heat shock proteins: The fountainhead of innate and adaptive immune responses. Cell Stress Chaperones 2000; 5(5): 443-51
192. Binder RJ, Vatner R, Srivastava P. The heat-shock protein receptors: some answers and more questions. Tissue Antigens 2004; 64(4): 442-51.
193. Basu S, Binder RJ, Ramalingam T, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 2001; 14: 303-13.
194. Triantafilou M, Triantafilou K. Heat-shock protein 70 and heat shock protein 90 associate with Toll-like receptor 4 in response to bacterial lipopolysaccharide. Biochem Soc Trans 2004; 32(Pt4): 636-9.
195. Ferrarini M, Heltai S, Zocchi MR, Rugarli C. Unusual expression and localization of heat-shock proteins in human tumor cells. Int J Cancer 1992; 51(4): 613-9.
196. Sapozhnikov AM, Ponomarev ED, Tarasenko TN, Telford WG. Spontaneous apoptosis and expression of cell surface heat-shock proteins in cultured EL-4 lymphoma cells. Cell Prolif 1999; 32(6): 363-78.
197. Sidera K, Patsavoudi E. Extracellular HSP90: An emerging target for cancer therapy Curr Signal Transd Ther 2009; 4(1): 51-8.
198. Eustace BK, Sakurai T, Stewart JK, Yimlamai D, Unger C, Zehetmeier C, et al. Functional proteomic screens reveal an essential extracellular role for HSP90 alpha in cancer cell invasiveness. Nat Cell Biol 2004; 6(6):507-14.
199. Tsutsumi S, Neckers L. Extracellular heat shock protein 90: A role for a molecular chaperone in cell motility and cancer metastasis. Cancer Sci 2007; 98(10): 1536-9.
200. McCready J, Sims JD, Chan D, Jay DG. Secretion of extracellular HSP90α via exosomes increases cancer cell motility: A role for plasminogen activation. BMC Cancer 2010; 10: 294.
201. Jay, D.G. Eustace, B.K., Sakurai, T. Inhibitors of extracellular HSP90. US20110150881 (2011).
202. Tsutsumi S, Scroggins B, Koga F, Lee M-J, Trepel J, Felts S, et al. A small molecule cell impermeant HSP90 antagonist inhibits tumor cell motility and invasion. Oncogene 2008; 27(17): 2478-87.
203. Vaughn CK, Mollapour M, Smith JR, Truman A, Hu B, Good VM, et al. HSP90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Mol Cell 2008; 31(6):886-95.
204. Pearl LH. HSP90 and Cdc37-a chaperone cancer conspiracy. Curr Opin Genet Dev 2005; 15(1): 55-61.
205. Gray PJJ, Prince T, Cheng J, Stevenson MA, Calderwood SK. The oncogene Cdc37 is a molecular chaperone: Targeting the kinome's favorite aunt. Nat Rev Cancer 2008; 8(7): 491-5.
206. Yang H, Chen D, Cui ZC, Yuan X, Dou WP. Celastrol, a triterpene extracted from the Chinese "thunder of god vine, " is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res 2006; 66(9):4758-65.
207. Zhang T, Hamza A, Cao X, Wang B, Yu S, Zhan C-G, Sun D. A novel HSP90 inhibitor to disrupt HSP90/Cdc37 complex against pancreatic cancer cells. Mol Cancer Ther 2008; 78(1): 162-70.
208. Sreeramulu S, Gande SL, Gobel M, Schwalbe H. Molecular mechanism of inhibition of the human protein complex HSP90-Cdc37, a kinome chaperone-cochaperone, by triterpene celastrol. Angew Chem Int Ed 2009; 48(32): 5853-5.
209. Hieronymus H, Lamb J, Ross KN, Peng XP, Clement C, Rodina A, et al. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell 2006; 10(4): 321-30.
210. Trott A, West JD, Klaic L, Westerheide SD, Silverman RB, Morimoto RI, et al. Activation of heat shock and antioxidant responses by the natural product celastrol: Transcriptional signatures of a thiol-targeted molecule. Mol Biol Cell 2008; 19(3):1104-12.
211. Vinson-Hieronymus, H., Golub, T.R., Lamb, J., Stegmaier, K. Celastrol, gedunin, and derivatives thereof as HSP90 inhibitor. WO2007117466 (2007).
212. Ronai, Z., A., Bhoumik, A., Cosford, N.D.P., Dahl, R. Compositions and methods for inhibiting growth and metastasis of melanoma. WO2009026163 (2009).
213. Cai, S.X., Zhang, H.-Z., Kasibhatla, S., Gaeta, F.C. Gambogic acid, analogs and derivatives as activators of caspases and inducers of apoptosis. US6462041 (2000).
214. Zhang H-Z, Kasibhatla S, Wang Y, Herich J, Guastella J, et al. Discovery, characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay. Bioorg Med Chem 2004; 12(2): 309-17.
215. Theodorakis, E., Ayse, B.A. Small molecule therapeutics, synthesis of analogs and derivatives and methods of use. US20100137421 (2008).
216. Davenport J, Manjarrez JR, Peterson L, Krumm B, Blagg BSJ, Matts RL. Gambogic acid, a natural product inhibitor of HSP90. J Nat Prod 2011; 74: 1085-92.
217. Moareffi, I., Scheufler, C., Hartl, U., Brinker, A. 3D structure of polypeptides containing a TPR-structure motif with chaperonebinding function, crystal thereof an compounds for inhibition of said peptides. WO0173019 (2001).
218. Scheufler C, Brinker A, Bourenkov G, Pegoraro S, Moroder L, Bartunik H, et al. Structure of TPR domain-peptide complexes: Critical elements in the assembly of the HSP70-HSP90 multichaperone machine. Cell 2000; 101(2):199-210.
219. Cortajarena AL, Yi F, Regan L. Designed TPR modules as novel anticancer agents. ACS Chem Biol 2008; 3(3): 161-6.
220. Yi F, Regan L. A novel class of small molecule inhibitors of HSP90. ACS Chem Biol 2008; 3(10): 645-54.
221. Yi F, Zhu P, Southall N, Inglese J, Austin CP, Zheng W, Regan L. An Alphascreen-based high-throughput screen to identify inhibitors of HSP90-cochaperone interaction. J Biomol Screen 2009; 14(3): 273-81.
222. Kawakami, K., Kohno M., Horibe, T. Novel HSP90-targeted anticancer chimeric peptide. WO201005592 (2010).
223. Horibe T, Kohno M, Haramoto M, Ohara K, Kawakami K. Designed hybrid TPR peptide targeting HSP90 as a novel anticancer agent. J Transl Med 2011; 9: 8.
224. Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional and therapeutic biology of survivin. Cancer Lett 2006; 244 (2): 164-71.
225. Altieri, D., Plescia, J., Saltz, W. Compounds that inhibit HSP90 protein-protein interactions with IAP proteins. WO200601474 (2006).
226. Plescia J, Salz W, Xia F, Pennati M, Zaffaroni N, Daidone MG, et al. Rational design of shepherdin, a novel anticancer agent. Cancer Cell 2005; 7(5): 457-68.
227. Gyurkocza B, Plescia J, Raskett CM, Garlick DS, Lowry PA, Carter BZ, et al. Antileukemic activity of shepherdin and molecular diversity of HSP90 inhibitors. J Natl Cancer Inst 2006; 98(15): 1068-77
228. Pritchard, K.A., Xu, H., Shi, Y. HSP90 decoy peptides and uses thereof. US20070219129 (2007).
229. Silverman, R.B., Liu, S., Gu, W., Adrian, T.E., Soff, G.A. Cyclic peptide antitumor agents. US20100204088 (2010).
230. Alexander LD, Sellers RP, Davis MR, Ardi VC, Johnson VA, et al. Evaluation of di-Sansalvamide A derivatives: Synthesis, structureactivity relationship, and mechanism of action. J Med Chem 2009; 52(24): 7927-30
231. Vasko RC, Rodriguez RA, Cunningham CN, Ardi VC, Agard DA, McAlpine SR. Mechanistic studies of Sansalvamide A-amide: an allosteric modulator of HSP90. Med Chem Lett 2010; 1(1): 4-8.
232. ChakrabortyA, Koldobskly MA, Sixt KM, Juluri KR, Mustafa AK, Snowman AM, et al. HSP90 regulates cell survival via inositol hexakisphosphate kinase-2. Proc Natl Acad Sci USA 2008; 105(4): 1134-9.