Heat shock protein-90 inhibitor

Hanson BE, Vesole DH. (2009) Retaspimycin hydrochloride (IPI-504) A novel heat shock protein inhibitor as an anticancer agent. Expert Opin Inv Drugs 18 1375-1383. 

Hur E, Kim HH, Choi SM, Kim JH, Yim S, Kwon HJ, Choi Y, Kim DK, Lee MO, Park H. Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-lalpha/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol. Mol. Pharmacol. 2002 62 975-982. 

Similar to nNOS, Ca2+-activated calmodulin is important for the regulation of eNOS activity. However, several other proteins interact with eNOS and regulate its activity. Heat shock protein 90 (hsp90) is found associated with eNOS and probably acts as an allosteric modulator that activates the enzyme. Caveolin-1 binds eNOS and directs it to caveolae. Caveolin-1 is viewed as an inhibitor of eNOS activity, which is being replaced by CaM upon activation of endothelial cells [2]. 

Antiapoptotic proteins. There are many different intracellular proteins that can prevent apoptosis by inhibiting specific steps in the cell death process. These include Bcl-2 family members such as Bcl-2 and Bcl-xL which can stabilize (mitochondrial, ER and plasma) membranes (Bcl-2 may also have intrinsic antioxidant activity). Other proteins, IAPs such as XIAP (X-linked) and NIAP (neuronal), which can directly inhibit caspases [31]. Additional examples of antiapoptotic proteins include protease inhibitors such as calpastatin, and protein chaperones such as GRP-78 and heat shock protein (HSP)-70. 

Powers, M.V. and Workman, P. (2006) Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocrine-Related Cancer, 13 (Suppl. 1), S125-S135. 

Moscinski L, Atadja P, Bhalla K (2004) Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 10 4991 997 Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumarawsamy S, Boyapalle S, Atadja P, Seto E, Bhalla K (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280(29) 26729-26734 Bannister AJ, Schneider R, Kouzarides T (2002) Histone methylation Dynamic or static Cell 109 801-806... 

Stresgenin B (inhibitor of heat shock proteins) Streptomyces sp. AS-9 88 370... 

Atadja, P., Seto, E. and Bhalla, K. (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 a novel basis for antileukemra activity of histone deacetylase inhibitors. The Journal of Biological Chemistry, 280, 26729-26734. 

Eccles SA, Massey A, Raynaud El et al (2008) NVP-AUY922 a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 68 2850-2860... 

Hu W, Wu W, Verschraegen CF, Chen L, Mao L, Yeung SC, Kudelka AP, Freedman RS, Kavanagh JJ. Proteomic identification of heat shock protein 70 as a candidate target for enhancing apoptosis induced by farnesyl transferase inhibitor. Proteomics 2003 3 1904-1911. 

Rowlands, M.G. et al. 2004. High-throughput screening assay for inhibitors of heat-shock protein 90 ATPase activity. Anal. Biochem. 327, 176-183. 

Zhou, V. et al. 2004. A time-resolved fluorescence resonance energy transfer-based HTS assay and a surface plasmon resonance-based binding assay for heat shock protein 90 inhibitors. Anal. Biochem. 331, 349-357. 

In summary, the KinaTor technology appears to be extremely potent for potentially revealing all binding partners of biologically active kinase inhibitors. Transmembrane domain proteins bind, as well as lipid kinases and other nucleotidebinding proteins, such as heat-shock proteins and oxidoreductases (unpublished data). So far, there are no limitations. 

Other mechanisms of action involve inhibitors of the heat shock protein Hsp-90, of checkpoint kinases, and inhibitors of protein degradation by interaction with the proteasome. 

Isaacs JS. Heat-shock protein 90 inhibitors in antineoplastic ther- 77. apy is it all wrapped up Exp. Opin. Investig. Drugs 2005 14 ... 

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