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Chemical Compound Review

AC1NUQQB     [ (3S,5R,6S,7R,8E,10S,11R,12Z,14 E)-6...

Synonyms: NSC330507, 17-AAG, 75747-14-7
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Disease relevance of NSC330507


High impact information on NSC330507


Chemical compound and disease context of NSC330507


Biological context of NSC330507


Anatomical context of NSC330507

  • Treatment with 17-AAG of the mast cell line HMC-1.2, harboring the Asp816Val and Val560Gly KIT mutations, and the cell line HMC-1.1, harboring a single Val560Gly mutation, causes both the level and activity of KIT and downstream signaling molecules AKT and STAT3 to be down-regulated following drug exposure [2].
  • 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells [2].
  • Cotreatment with LBH589 and 17-AAG exerted synergistic apoptosis of MV4-11 and K562 cells [14].
  • Treatment with 17-AAG triggered the B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) conformational change associated with apoptosis, while Bax-deficient cells were resistant to 17-AAG-induced apoptosis [3].
  • Simultaneous exposure (30 hours) of U937 monocytic leukemia cells to minimally toxic concentrations of 17-AAG (eg, 400 nM) and UCN-01 (eg, 75 nM) triggered a pronounced increase in mitochondrial injury (ie, loss of mitochondrial membrane potential [Deltapsim]; cytosolic release of cytochrome c), caspase activation, and apoptosis [15].

Associations of NSC330507 with other chemical compounds

  • Treatment with Hsp90 inhibitors such as 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) induced ZAP-70 degradation and apoptosis in CLL cells but not in T cells, and also impaired B-cell receptor signaling in leukemia cells [16].
  • Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine-induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis [17].
  • Cells expressing high levels of Nm23-H1 exhibited increased KSR1 degradation in the presence of either cycloheximide or an Hsp90-directed drug currently in clinical trial, 17-allylamino-17-demethoxygeldanamycin (17-AAG) [18].
  • 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a conserved pocket in Hsp90 and induces the degradation of proteins that require this chaperone for conformational maturation [19].
  • In addition to 17-AAG, other Hsp90 inhibitors, such as radicicol and herbimycin A, also enhanced osteoclastogenesis [20].

Gene context of NSC330507

  • Interactions between the protein kinase C (PKC) and Chk1 inhibitor UCN-01 and the heat shock protein 90 (Hsp90) antagonist 17-AAG have been examined in human leukemia cells in relation to effects on signal transduction pathways and apoptosis [15].
  • Together, these findings indicate that the Hsp90 antagonist 17-AAG potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types and suggest that interference with both the Akt and Raf-1/MEK/MAP kinase cytoprotective signaling pathways contribute to this phenomenon [15].
  • Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways [15].
  • In addition, inducible expression of both a constitutively active MEK1/2 or myristolated Akt construct, which overcame inhibition of ERK and Akt activation, respectively, significantly attenuated 17-AAG/UCN-01-mediated lethality [15].
  • High-performance liquid chromatography (HPLC) analysis of the metabolism of 17-AAG by recombinant human NQO1 revealed the formation of a more polar metabolite 17-AAGH2 [21].

Analytical, diagnostic and therapeutic context of NSC330507

  • Phase II clinical trials in various cancers have been initiated as well as Phase I trials of combined therapy with 17-AAG [4].
  • In addition, 17-AAG significantly inhibited the growth of a glioma xenograft in nude mice [9].
  • Therefore, tumors that are dependent on these kinases may be especially sensitive to 17-AAG either alone or in combination with chemotherapy [22].
  • CONCLUSION: It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m(2)/week [23].
  • HPLC analysis of 17-AAG metabolism using cell sonicates and intact cells showed that 17-AAGH2 was formed by MDA468/NQ16 cells, and formation of 17-AAGH2 could be inhibited by ES936 [21].


  1. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Waza, M., Adachi, H., Katsuno, M., Minamiyama, M., Sang, C., Tanaka, F., Inukai, A., Doyu, M., Sobue, G. Nat. Med. (2005) [Pubmed]
  2. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. Fumo, G., Akin, C., Metcalfe, D.D., Neckers, L. Blood (2004) [Pubmed]
  3. Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases. Nimmanapalli, R., O'Bryan, E., Kuhn, D., Yamaguchi, H., Wang, H.G., Bhalla, K.N. Blood (2003) [Pubmed]
  4. Inhibitors of the HSP90 molecular chaperone: current status. Sharp, S., Workman, P. Adv. Cancer Res. (2006) [Pubmed]
  5. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Sydor, J.R., Normant, E., Pien, C.S., Porter, J.R., Ge, J., Grenier, L., Pak, R.H., Ali, J.A., Dembski, M.S., Hudak, J., Patterson, J., Penders, C., Pink, M., Read, M.A., Sang, J., Woodward, C., Zhang, Y., Grayzel, D.S., Wright, J., Barrett, J.A., Palombella, V.J., Adams, J., Tong, J.K. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  6. Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. Grem, J.L., Morrison, G., Guo, X.D., Agnew, E., Takimoto, C.H., Thomas, R., Szabo, E., Grochow, L., Grollman, F., Hamilton, J.M., Neckers, L., Wilson, R.H. J. Clin. Oncol. (2005) [Pubmed]
  7. Geldanamycin and its 17-allylamino-17-demethoxy analogue antagonize the action of Cisplatin in human colon adenocarcinoma cells: differential caspase activation as a basis for interaction. Vasilevskaya, I.A., Rakitina, T.V., O'Dwyer, P.J. Cancer Res. (2003) [Pubmed]
  8. Molecular characterization and sensitivity of STI-571 (imatinib mesylate, Gleevec)-resistant, Bcr-Abl-positive, human acute leukemia cells to SRC kinase inhibitor PD180970 and 17-allylamino-17-demethoxygeldanamycin. Nimmanapalli, R., O'Bryan, E., Huang, M., Bali, P., Burnette, P.K., Loughran, T., Tepperberg, J., Jove, R., Bhalla, K. Cancer Res. (2002) [Pubmed]
  9. Disruption of the EF-2 kinase/Hsp90 protein complex: a possible mechanism to inhibit glioblastoma by geldanamycin. Yang, J., Yang, J.M., Iannone, M., Shih, W.J., Lin, Y., Hait, W.N. Cancer Res. (2001) [Pubmed]
  10. Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling. Rakitina, T.V., Vasilevskaya, I.A., O'Dwyer, P.J. Cancer Res. (2003) [Pubmed]
  11. Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. George, P., Bali, P., Cohen, P., Tao, J., Guo, F., Sigua, C., Vishvanath, A., Fiskus, W., Scuto, A., Annavarapu, S., Moscinski, L., Bhalla, K. Cancer Res. (2004) [Pubmed]
  12. Coadministration of the heat shock protein 90 antagonist 17-allylamino- 17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. Rahmani, M., Yu, C., Dai, Y., Reese, E., Ahmed, W., Dent, P., Grant, S. Cancer Res. (2003) [Pubmed]
  13. Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Solit, D.B., Basso, A.D., Olshen, A.B., Scher, H.I., Rosen, N. Cancer Res. (2003) [Pubmed]
  14. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. George, P., Bali, P., Annavarapu, S., Scuto, A., Fiskus, W., Guo, F., Sigua, C., Sondarva, G., Moscinski, L., Atadja, P., Bhalla, K. Blood (2005) [Pubmed]
  15. Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways. Jia, W., Yu, C., Rahmani, M., Krystal, G., Sausville, E.A., Dent, P., Grant, S. Blood (2003) [Pubmed]
  16. ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Castro, J.E., Prada, C.E., Loria, O., Kamal, A., Chen, L., Burrows, F.J., Kipps, T.J. Blood (2005) [Pubmed]
  17. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine. Mesa, R.A., Loegering, D., Powell, H.L., Flatten, K., Arlander, S.J., Dai, N.T., Heldebrant, M.P., Vroman, B.T., Smith, B.D., Karp, J.E., Eyck, C.J., Erlichman, C., Kaufmann, S.H., Karnitz, L.M. Blood (2005) [Pubmed]
  18. Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells. Salerno, M., Palmieri, D., Bouadis, A., Halverson, D., Steeg, P.S. Mol. Cell. Biol. (2005) [Pubmed]
  19. Inhibition of heat shock protein 90 function by ansamycins causes the morphological and functional differentiation of breast cancer cells. Münster, P.N., Srethapakdi, M., Moasser, M.M., Rosen, N. Cancer Res. (2001) [Pubmed]
  20. The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line. Price, J.T., Quinn, J.M., Sims, N.A., Vieusseux, J., Waldeck, K., Docherty, S.E., Myers, D., Nakamura, A., Waltham, M.C., Gillespie, M.T., Thompson, E.W. Cancer Res. (2005) [Pubmed]
  21. Formation of 17-allylamino-demethoxygeldanamycin (17-AAG) hydroquinone by NAD(P)H:quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibition. Guo, W., Reigan, P., Siegel, D., Zirrolli, J., Gustafson, D., Ross, D. Cancer Res. (2005) [Pubmed]
  22. Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway. Münster, P.N., Marchion, D.C., Basso, A.D., Rosen, N. Cancer Res. (2002) [Pubmed]
  23. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. Banerji, U., O'Donnell, A., Scurr, M., Pacey, S., Stapleton, S., Asad, Y., Simmons, L., Maloney, A., Raynaud, F., Campbell, M., Walton, M., Lakhani, S., Kaye, S., Workman, P., Judson, I. J. Clin. Oncol. (2005) [Pubmed]
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