New dihydropyrimidin-2(1H)-one based Hsp90 C-terminal inhibitors

RSC Advances ◽  
2016 ◽  
Vol 6 (85) ◽  
pp. 82330-82340 ◽  
Author(s):  
S. Terracciano ◽  
A. Foglia ◽  
M. G. Chini ◽  
M. C. Vaccaro ◽  
A. Russo ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Therapy ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
New Class ◽  
Terminal Domain ◽  
Novel Strategy

The inhibition of the C-terminal domain of heat shock protein 90 (Hsp90) is emerging as a novel strategy for cancer therapy, therefore the identification of a new class of C-terminal inhibitors is strongly required.

scholarly journals The Amino-terminal Domain of Heat Shock Protein 90 (hsp90) That Binds Geldanamycin Is an ATP/ADP Switch Domain That Regulates hsp90 Conformation

1997 ◽  
Vol 272 (38) ◽  
pp. 23843-23850 ◽  
Author(s):  
James P. Grenert ◽  
William P. Sullivan ◽  
Patrick Fadden ◽  
Timothy A. J. Haystead ◽  
Jenny Clark ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Amino Terminal Domain

scholarly journals Discovery of aminoquinolines as a new class of potent inhibitors of heat shock protein 90 (Hsp90): Synthesis, biology, and molecular modeling

2008 ◽  
Vol 16 (14) ◽  
pp. 6903-6910 ◽  
Author(s):  
Thota Ganesh ◽  
Jaeki Min ◽  
Pahk Thepchatri ◽  
Yuhong Du ◽  
Lian Li ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
New Class

scholarly journals Dimerization and N-terminal domain proximity underlie the function of the molecular chaperone heat shock protein 90

2000 ◽  
Vol 97 (23) ◽  
pp. 12524-12529 ◽  
Author(s):  
A. Chadli ◽  
I. Bouhouche ◽  
W. Sullivan ◽  
B. Stensgard ◽  
N. McMahon ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Molecular Chaperone ◽  
Heat Shock Protein 90 ◽  
Terminal Domain

scholarly journals Functional characterization of heat-shock protein 90 fromOryza sativaand crystal structure of its N-terminal domain

2015 ◽  
Vol 71 (6) ◽  
pp. 688-696 ◽  
Author(s):  
Swetha Raman ◽  
Kaza Suguna
Keyword(s):  
Crystal Structure ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Biochemical Characterization ◽  
Functional Characterization ◽  
Cell Signalling ◽  
Physiological Role ◽  
Heat Shock Protein 90 ◽  
Terminal Domain

Heat-shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that is essential for the normal functioning of eukaryotic cells. It plays crucial roles in cell signalling, cell-cycle control and in maintaining proteome integrity and protein homeostasis. In plants, Hsp90s are required for normal plant growth and development. Hsp90s are observed to be upregulated in response to various abiotic and biotic stresses and are also involved in immune responses in plants. Although there are several studies elucidating the physiological role of Hsp90s in plants, their molecular mechanism of action is still unclear. In this study, biochemical characterization of an Hsp90 protein from rice (Oryza sativa; OsHsp90) has been performed and the crystal structure of its N-terminal domain (OsHsp90-NTD) was determined. The binding of OsHsp90 to its substrate ATP and the inhibitor 17-AAG was studied by fluorescence spectroscopy. The protein also exhibited a weak ATPase activity. The crystal structure of OsHsp90-NTD was solved in complex with the nonhydrolyzable ATP analogue AMPPCP at 3.1 Å resolution. The domain was crystallized by cross-seeding with crystals of the N-terminal domain of Hsp90 fromDictyostelium discoideum, which shares 70% sequence identity with OsHsp90-NTD. This is the second reported structure of a domain of Hsp90 from a plant source.

Heat-shock protein 90 inhibitors in cancer therapy: 17AAG and beyond

2005 ◽  
Vol 1 (2) ◽  
pp. 273-281 ◽  
Author(s):  
Anas Younes ◽  
Georgios V Georgakis
Keyword(s):  
Heat Shock ◽  
Cancer Therapy ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90

scholarly journals Heat shock protein 90 inhibition by 17-DMAG attenuates abdominal aortic aneurysm formation in mice

2015 ◽  
Vol 308 (8) ◽  
pp. H841-H852 ◽  
Author(s):  
Jia Qi ◽  
Ping Yang ◽  
Bing Yi ◽  
Yan Huo ◽  
Ming Chen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Heat Shock ◽  
Aortic Aneurysm ◽  
Heat Shock Protein ◽  
Vascular Inflammation ◽  
Heat Shock Protein 90 ◽  
Ang Ii ◽  
Iκb Kinase ◽  
Abdominal Aortic ◽  
Novel Strategy

Abdominal aortic aneurysm (AAA) is a common degenerative vascular disease whose pathogenesis is associated with activation of multiple signaling pathways including Jun NH2-terminal kinases (JNK) and NF-κB. It is now well recognized that these pathways are chaperoned by the heat shock protein 90 (Hsp90), suggesting that inhibition of Hsp90 may be a novel strategy for inhibiting AAAs. The aim of this study is to investigate whether inhibition of Hsp90 by 17-DMAG (17-dimethyl-aminothylamino-17-demethoxy-geldanamycin) attenuates ANG II-induced AAA formation in mice, and, if so, to elucidate the mechanisms involved. Apolipoprotein E-null mice were infused with ANG II to induce AAA formation and simultaneously treated by intraperitoneal injection with either vehicle or 17-DMAG for 4 wk. ANG II infusion induced AAA formation in 80% of mice, which was accompanied by increased matrix metalloproteinase (MMP) activity, enhanced tissue inflammation, oxidative stress, and neovascularization. Importantly, these effects were inhibited by 17-DMAG treatment. Mechanistically, we showed that 17-DMAG prevented the formation and progression of AAA through its inhibitory effects on diverse biological pathways including 1) by blocking ANG II-induced phosphorylation of ERK1/2 and JNK that are critically involved in the regulation of MMPs in vascular smooth muscle cells, 2) by inhibiting IκB kinase expression and expression of MCP-1, and 3) by attenuating ANG II-stimulated angiogenic processes critical to AAA formation. Our results demonstrate that inhibition of Hsp90 by 17-DMAG effectively attenuates ANG II-induced AAA formation by simultaneously inhibiting vascular inflammation, extracellular matrix degradation, and angiogenesis, which are critical in the formation and progression of AAAs.

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