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Chemical Compound Review

AC1L235A     [(3S,5R,6S,7R,10S,11R)-6- hydroxy-5,11,21...

Synonyms: NCI60_000537
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Disease relevance of C11222


Psychiatry related information on C11222


High impact information on C11222

  • In vivo, geldanamycin activates HSF1 under conditions in which it is an Hsp90-specific reagent [7].
  • The structure of the geldanamycin-binding domain of Hsp90 (residues 9-232) reveals a pronounced pocket, 15 A deep, that is highly conserved across species [8].
  • Geldanamycin (GA), an antitumor agent that disrupts the formation of this heterocomplex, prevents TNF-induced activation of IKK and NF-kappaB [9].
  • In addition, vaccination with irradiated cells secreting the GRP94 NH(2)-terminal geldanamycin-binding domain (NTD), a region lacking canonical peptide-binding motifs, yielded a similar suppression of tumor growth and metastatic progression [10].
  • Geldanamycin, an inhibitor of hsp90, almost completely suppressed OVA antigen presentation in PA28alpha(-/-)/beta(-/-) lipopolysaccharide blasts, but not in wild-type cells, indicating that hsp90 compensates for the loss of PA28 and is essential in the PA28-independent pathway [11].

Chemical compound and disease context of C11222


Biological context of C11222


Anatomical context of C11222

  • Immunoconjugates of geldanamycin and anti-HER2 monoclonal antibodies: antiproliferative activity on human breast carcinoma cell lines [22].
  • We show that the ansamysin drugs, geldanamycin and herbimycin A, which inhibit the assembly of some signaling molecules by binding to specific sites on Hsp90 in the cytosol or Grp94 in the ER lumen, block the maturation of nascent CFTR and accelerate its degradation [23].
  • Using this system and a fluorescence recovery after photobleaching technique, we demonstrate that nuclear mobility of GR recovered on incubation with reticulocyte lysate was inhibited by geldanamycin, a drug that blocks the chaperone activity of heat-shock protein 90 [24].
  • Geldanamycin, a specific inhibitor of the Hsp 90 family, blocked the nuclear translocation of NF-kappaB and expression of tumor necrosis factor in macrophages treated with Taxol or with LPS [21].
  • Here we establish that following TCR stimulation, endogenous activated Lck in T cells is also degraded in the presence of the Hsp90 inhibitor geldanamycin [25].

Associations of C11222 with other chemical compounds

  • A carboxy-terminal Hsp90 fragment bound immobilized novobiocin but not immobilized geldanamycin, while a geldanamycin-binding amino-terminal fragment did not bind novobiocin [26].
  • The first-in-class HSP90 inhibitor in clinical trials is the geldanamycin analog, 17-allylamino, 17-demethoxygeldanamycin (17-AAG) [27].
  • Topics covered include the mechanisms of action of inhibitors of topoisomerases I and II; the immunosuppressants rapamycin, cyclosporin A, and FK506; the phosphatidylinositol 3-kinase inhibitor wortmannin; the angiogenesis inhibitors fumagillin and ovalicin; the HSP90 inhibitor geldanamycin; and agents that inhibit sphingolipid metabolism [28].
  • When stable transfectants of p53-143ala were prepared in yeast expressing wild-type HSP90, conformational recognition of mutated p53 was antagonized by macbecin I, a geldanamycin analog also known to bind HSP90 [29].
  • To examine the effect of directly disrupting chaperone interactions with mutant p53, we made use of geldanamycin (GA), a selective hsp90-binding agent which has been shown to alter the chaperone associations regulating the function of unliganded steroid receptors [30].

Gene context of C11222

  • Here we show that disruption of Hsp90 by geldanamycin promotes efficient ubiquitination and proteasome-mediated degradation of hTERT [31].
  • We find that the alphaGDI-chaperone complex is dissociated in response to Ca(2+)-induced neurotransmitter release, that chaperone complex dissociation is sensitive to the Hsp90 inhibitor geldanamycin (GA) and that GA inhibits the ability of alphaGDI to recycle Rab3A during neurotransmitter release [32].
  • A short-term exposure of cells to the Hsp90 inhibitors GA or radicicol not only derepresses PKR, but also activates the Raf-MAPK pathway [33].
  • GA also blocked the VEGF-induced Hsp90 binding to APAF-1 on leukemic cells, a mechanism shown to inhibit apoptosis [34].
  • However, we show here that geldanamycin blocks the development of aggregates of the expanded glutamine androgen receptor (AR112Q) of Kennedy disease in Hsf1(-/-) mouse embryonic fibroblasts where these chaperones are not induced [35].

Analytical, diagnostic and therapeutic context of C11222


  1. Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone. Zhao, R., Davey, M., Hsu, Y.C., Kaplanek, P., Tong, A., Parsons, A.B., Krogan, N., Cagney, G., Mai, D., Greenblatt, J., Boone, C., Emili, A., Houry, W.A. Cell (2005) [Pubmed]
  2. ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo. Panaretou, B., Prodromou, C., Roe, S.M., O'Brien, R., Ladbury, J.E., Piper, P.W., Pearl, L.H. EMBO J. (1998) [Pubmed]
  3. HSP90 interacts with RAR1 and SGT1 and is essential for RPS2-mediated disease resistance in Arabidopsis. Takahashi, A., Casais, C., Ichimura, K., Shirasu, K. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Phenotypic change from transformed to normal induced by benzoquinonoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus. Uehara, Y., Hori, M., Takeuchi, T., Umezawa, H. Mol. Cell. Biol. (1986) [Pubmed]
  5. p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function. Grammatikakis, N., Lin, J.H., Grammatikakis, A., Tsichlis, P.N., Cochran, B.H. Mol. Cell. Biol. (1999) [Pubmed]
  6. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. Sittler, A., Lurz, R., Lueder, G., Priller, J., Lehrach, H., Hayer-Hartl, M.K., Hartl, F.U., Wanker, E.E. Hum. Mol. Genet. (2001) [Pubmed]
  7. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Zou, J., Guo, Y., Guettouche, T., Smith, D.F., Voellmy, R. Cell (1998) [Pubmed]
  8. Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Stebbins, C.E., Russo, A.A., Schneider, C., Rosen, N., Hartl, F.U., Pavletich, N.P. Cell (1997) [Pubmed]
  9. TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Chen, G., Cao, P., Goeddel, D.V. Mol. Cell (2002) [Pubmed]
  10. GRP94 (gp96) and GRP94 N-terminal geldanamycin binding domain elicit tissue nonrestricted tumor suppression. Baker-LePain, J.C., Sarzotti, M., Fields, T.A., Li, C.Y., Nicchitta, C.V. J. Exp. Med. (2002) [Pubmed]
  11. Two distinct pathways mediated by PA28 and hsp90 in major histocompatibility complex class I antigen processing. Yamano, T., Murata, S., Shimbara, N., Tanaka, N., Chiba, T., Tanaka, K., Yui, K., Udono, H. J. Exp. Med. (2002) [Pubmed]
  12. The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells. Xu, W., Yuan, X., Jung, Y.J., Yang, Y., Basso, A., Rosen, N., Chung, E.J., Trepel, J., Neckers, L. Cancer Res. (2003) [Pubmed]
  13. Free and N-(2-hydroxypropyl)methacrylamide copolymer-bound geldanamycin derivative induce different stress responses in A2780 human ovarian carcinoma cells. Nishiyama, N., Nori, A., Malugin, A., Kasuya, Y., Kopecková, P., Kopecek, J. Cancer Res. (2003) [Pubmed]
  14. Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors. Beliakoff, J., Bagatell, R., Paine-Murrieta, G., Taylor, C.W., Lykkesfeldt, A.E., Whitesell, L. Clin. Cancer Res. (2003) [Pubmed]
  15. The heat-shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis. Russo, C.D., Polak, P.E., Mercado, P.R., Spagnolo, A., Sharp, A., Murphy, P., Kamal, A., Burrows, F.J., Fritz, L.C., Feinstein, D.L. J. Neurochem. (2006) [Pubmed]
  16. Bicarbonate-dependent superoxide release and pulmonary artery tone. Nozik-Grayck, E., Huang, Y.C., Carraway, M.S., Piantadosi, C.A. Am. J. Physiol. Heart Circ. Physiol. (2003) [Pubmed]
  17. Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. Citri, A., Alroy, I., Lavi, S., Rubin, C., Xu, W., Grammatikakis, N., Patterson, C., Neckers, L., Fry, D.W., Yarden, Y. EMBO J. (2002) [Pubmed]
  18. Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90. Okamoto, T., Nishimura, Y., Ichimura, T., Suzuki, K., Miyamura, T., Suzuki, T., Moriishi, K., Matsuura, Y. EMBO J. (2006) [Pubmed]
  19. Hsp90 is a core centrosomal component and is required at different stages of the centrosome cycle in Drosophila and vertebrates. Lange, B.M., Bachi, A., Wilm, M., González, C. EMBO J. (2000) [Pubmed]
  20. NQO1 stabilizes p53 through a distinct pathway. Asher, G., Lotem, J., Kama, R., Sachs, L., Shaul, Y. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  21. Heat shock protein 90 mediates macrophage activation by Taxol and bacterial lipopolysaccharide. Byrd, C.A., Bornmann, W., Erdjument-Bromage, H., Tempst, P., Pavletich, N., Rosen, N., Nathan, C.F., Ding, A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  22. Immunoconjugates of geldanamycin and anti-HER2 monoclonal antibodies: antiproliferative activity on human breast carcinoma cell lines. Mandler, R., Wu, C., Sausville, E.A., Roettinger, A.J., Newman, D.J., Ho, D.K., King, C.R., Yang, D., Lippman, M.E., Landolfi, N.F., Dadachova, E., Brechbiel, M.W., Waldmann, T.A. J. Natl. Cancer Inst. (2000) [Pubmed]
  23. Perturbation of Hsp90 interaction with nascent CFTR prevents its maturation and accelerates its degradation by the proteasome. Loo, M.A., Jensen, T.J., Cui, L., Hou, Y., Chang, X.B., Riordan, J.R. EMBO J. (1998) [Pubmed]
  24. Molecular chaperones function as steroid receptor nuclear mobility factors. Elbi, C., Walker, D.A., Romero, G., Sullivan, W.P., Toft, D.O., Hager, G.L., DeFranco, D.B. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  25. Regulation of the Src family kinase Lck by Hsp90 and ubiquitination. Giannini, A., Bijlmakers, M.J. Mol. Cell. Biol. (2004) [Pubmed]
  26. Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins. Marcu, M.G., Schulte, T.W., Neckers, L. J. Natl. Cancer Inst. (2000) [Pubmed]
  27. Inhibitors of the HSP90 molecular chaperone: current status. Sharp, S., Workman, P. Adv. Cancer Res. (2006) [Pubmed]
  28. Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action. Cardenas, M.E., Cruz, M.C., Del Poeta, M., Chung, N., Perfect, J.R., Heitman, J. Clin. Microbiol. Rev. (1999) [Pubmed]
  29. Mutant conformation of p53 translated in vitro or in vivo requires functional HSP90. Blagosklonny, M.V., Toretsky, J., Bohen, S., Neckers, L. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  30. The physical association of multiple molecular chaperone proteins with mutant p53 is altered by geldanamycin, an hsp90-binding agent. Whitesell, L., Sutphin, P.D., Pulcini, E.J., Martinez, J.D., Cook, P.H. Mol. Cell. Biol. (1998) [Pubmed]
  31. Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT. Kim, J.H., Park, S.M., Kang, M.R., Oh, S.Y., Lee, T.H., Muller, M.T., Chung, I.K. Genes Dev. (2005) [Pubmed]
  32. Rab-alphaGDI activity is regulated by a Hsp90 chaperone complex. Sakisaka, T., Meerlo, T., Matteson, J., Plutner, H., Balch, W.E. EMBO J. (2002) [Pubmed]
  33. The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR. Donzé, O., Abbas-Terki, T., Picard, D. EMBO J. (2001) [Pubmed]
  34. VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Dias, S., Shmelkov, S.V., Lam, G., Rafii, S. Blood (2002) [Pubmed]
  35. Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction. Thomas, M., Harrell, J.M., Morishima, Y., Peng, H.M., Pratt, W.B., Lieberman, A.P. Hum. Mol. Genet. (2006) [Pubmed]
  36. A biochemical rationale for the anticancer effects of Hsp90 inhibitors: slow, tight binding inhibition by geldanamycin and its analogues. Gooljarsingh, L.T., Fernandes, C., Yan, K., Zhang, H., Grooms, M., Johanson, K., Sinnamon, R.H., Kirkpatrick, R.B., Kerrigan, J., Lewis, T., Arnone, M., King, A.J., Lai, Z., Copeland, R.A., Tummino, P.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  37. Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection. Demidenko, Z.N., Vivo, C., Halicka, H.D., Li, C.J., Bhalla, K., Broude, E.V., Blagosklonny, M.V. Cell Death Differ. (2006) [Pubmed]
  38. Combination treatment with 17-N-allylamino-17-demethoxy geldanamycin and acute irradiation produces supra-additive growth suppression in human prostate carcinoma spheroids. Enmon, R., Yang, W.H., Ballangrud, A.M., Solit, D.B., Heller, G., Rosen, N., Scher, H.I., Sgouros, G. Cancer Res. (2003) [Pubmed]
  39. Bcl-xL is phosphorylated in malignant cells following microtubule disruption. Poruchynsky, M.S., Wang, E.E., Rudin, C.M., Blagosklonny, M.V., Fojo, T. Cancer Res. (1998) [Pubmed]
  40. Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. Mimnaugh, E.G., Chavany, C., Neckers, L. J. Biol. Chem. (1996) [Pubmed]
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