scholarly journals Correction: 2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition

2018 ◽  
Vol 16 (25) ◽  
pp. 4734-4734
Author(s):  
Kunal Nepali ◽  
Sunil Kumar ◽  
Hsiang-Ling Huang ◽  
Fei-Chiao Kuo ◽  
Cheng-Hsin Lee ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Anticancer Agents ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibition

Correction for ‘2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition’ by Kunal Nepali et al., Org. Biomol. Chem., 2016, 14, 716–723.

2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition

2016 ◽  
Vol 14 (2) ◽  
pp. 716-723 ◽  
Author(s):  
Kunal Nepali ◽  
Sunil Kumar ◽  
Hsiang-Ling Huang ◽  
Fei-Chiao Kuo ◽  
Cheng-Hsin Lee ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Anticancer Agents ◽  
Heat Shock Protein 90 ◽  
Scaffold Hopping ◽  
Hsp90 Inhibition

This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11–23) on the basis of scaffold hopping.

Effect of heat-shock protein-90 (HSP90) inhibition on human hepatocytes and on liver regeneration in experimental models

Surgery ◽  
2010 ◽  
Vol 147 (5) ◽  
pp. 704-712 ◽  
Author(s):  
Christina Hackl ◽  
Akira Mori ◽  
Christian Moser ◽  
Sven A. Lang ◽  
Rania Dayoub ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Liver Regeneration ◽  
Heat Shock Protein 90 ◽  
Experimental Models ◽  
Human Hepatocytes ◽  
Hsp90 Inhibition

Blocking the heat shock response and depleting HSF-1 levels through heat shock protein 90 (hsp90) inhibition: a significant advance on current hsp90 chemotherapies

RSC Advances ◽  
2015 ◽  
Vol 5 (73) ◽  
pp. 59003-59013 ◽  
Author(s):  
Yen Chin Koay ◽  
Jeanette R. McConnell ◽  
Yao Wang ◽  
Shelli R. McAlpine
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Response ◽  
Heat Shock Protein 90 ◽  
Significant Advance ◽  
Hsp90 Inhibition ◽  
C Terminus ◽  
Shock Response

C-terminal inhibitors of heat shock protein 90 (hsp90) modulate the C-terminus and do not elicit a heat shock response.

Structure based design of heat shock protein 90 inhibitors acting as anticancer agents

2011 ◽  
Vol 19 (5) ◽  
pp. 1714-1720 ◽  
Author(s):  
Munikumar Reddy Doddareddy ◽  
Dhanaji Achyutrao Thorat ◽  
Seon Hee Seo ◽  
Tae-Joon Hong ◽  
Yong Seo Cho ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Anticancer Agents ◽  
Heat Shock Protein 90

scholarly journals Heat shock protein 90 is involved in the regulation of HMGA2-driven growth and epithelial-to-mesenchymal transition of colorectal cancer cells

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e1683 ◽  
Author(s):  
Chun-Yu Kao ◽  
Pei-Ming Yang ◽  
Ming-Heng Wu ◽  
Chi-Chen Huang ◽  
Yi-Chao Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Protein Expression ◽  
Cancer Cells ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Mesenchymal Transition ◽  
Hmga2 Protein

High Mobility Group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein which acts as a transcriptional regulating factor involved in gene transcription. In particular, overexpression of HMGA2 has been demonstrated to associate with neoplastic transformation and tumor progression in Colorectal Cancer (CRC). Thus, HMGA2 is a potential therapeutic target in cancer therapy. Heat Shock Protein 90 (Hsp90) is a chaperone protein required for the stability and function for a number of proteins that promote the growth, mobility, and survival of cancer cells. Moreover, it has shown strong positive connections were observed between Hsp90 inhibitors and CRC, which indicated their potential for use in CRC treatment by using combination of data mining and experimental designs. However, little is known about the effect of Hsp90 inhibition on HMGA2 protein expression in CRC. In this study, we tested the hypothesis that Hsp90 may regulate HMGA2 expression and investigated the relationship between Hsp90 and HMGA2 signaling. The use of the second-generation Hsp90 inhibitor, NVP-AUY922, considerably knocked down HMGA2 expression, and the effects of Hsp90 and HMGA2 knockdown were similar. In addition, Hsp90 knockdown abrogates colocalization of Hsp90 and HMGA2 in CRC cells. Moreover, the suppression of HMGA2 protein expression in response to NVP-AUY922 treatment resulted in ubiquitination and subsequent proteasome-dependant degradation of HMGA2. Furthermore, RNAi-mediated silencing of HMGA2 reduced the survival of CRC cells and increased the sensitivity of these cells to chemotherapy. Finally, we found that the NVP-AUY922-dependent mitigation of HMGA2 signaling occurred also through indirect reactivation of the tumor suppressor microRNA (miRNA), let-7a, or the inhibition of ERK-regulated HMGA2 involved in regulating the growth of CRC cells. Collectively, our studies identify the crucial role for the Hsp90-HMGA2 interaction in maintaining CRC cell survival and migration. These findings have significant implications for inhibition HMGA2-dependent tumorigenesis by clinically available Hsp90 inhibitors.

scholarly journals Mutational Analysis of Glycogen Synthase Kinase 3β Protein Kinase Together with Kinome-Wide Binding and Stability Studies Suggests Context-Dependent Recognition of Kinases by the Chaperone Heat Shock Protein 90

2016 ◽  
Vol 36 (6) ◽  
pp. 1007-1018 ◽  
Author(s):  
Jing Jin ◽  
Ruijun Tian ◽  
Adrian Pasculescu ◽  
Anna Yue Dai ◽  
Kelly Williton ◽  
...  
Keyword(s):  
Heat Shock ◽  
Protein Kinase ◽  
Heat Shock Protein ◽  
Cell Lines ◽  
Glycogen Synthase ◽  
Heat Shock Protein 90 ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Hsp90 Inhibition ◽  
Context Dependent

The heat shock protein 90 (HSP90) and cell division cycle 37 (CDC37) chaperones are key regulators of protein kinase folding and maturation. Recent evidence suggests that thermodynamic properties of kinases, rather than primary sequences, are recognized by the chaperones. In concordance, we observed a striking difference in HSP90 binding between wild-type (WT) and kinase-dead (KD) glycogen synthase kinase 3β (GSK3β) forms. Using model cell lines stably expressing these two GSK3β forms, we observed no interaction between WT GSK3β and HSP90, in stark contrast to KD GSK3β forming a stable complex with HSP90 at a 1:1 ratio. In a survey of 91 ectopically expressed kinases in DLD-1 cells, we compared two parameters to measure HSP90 dependency: static binding and kinase stability following HSP90 inhibition. We observed no correlation between HSP90 binding and reduced stability of a kinase after pharmacological inhibition of HSP90. We expanded our stability study to >50 endogenous kinases across four cell lines and demonstrated that HSP90 dependency is context dependent. These observations suggest that HSP90 binds to its kinase client in a particular conformation that we hypothesize to be associated with the nucleotide-processing cycle. Lastly, we performed proteomics profiling of kinases and phosphopeptides in DLD-1 cells to globally define the impact of HSP90 inhibition on the kinome.

Phase II trial of tanespimycin (KOS-953), a heat shock protein-90 (Hsp90) inhibitor in patients with metastatic melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8558-8558 ◽  
Author(s):  
R. Kefford ◽  
M. Millward ◽  
P. Hersey ◽  
B. Brady ◽  
M. Graham ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Single Agent ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Heat Shock Protein 90 ◽  
Clinical Activity ◽  
Hsp90 Inhibition

8558 Background: Tanespimycin binds to and inhibits the activity of Heat Shock Protein 90 (Hsp90). Hsp90 inhibition results in the degradation of a variety of RAF family proteins, including mutant BRAF. As the majority of melanomas have activation of the BRAF-MAPK pathway, we postulate that tanespimycin will interrupt the MAPK pathway and may lead to clinically significant anti-melanoma effects. Methods: This is a multi-center two-stage Simon design study; continuation to the second stage required at least 1 pt with progression free survival (PFS) of at least 24 weeks (the primary endpoint of this trial). Eligibility: pts with stage M1 melanoma, measurable/unresectable disease, up to 1 prior chemotherapy treatment for metastatic disease and ECOG PS 0 or 1. Tanespimycin (275 mg/m2 IV) was given D1,4,8,11 q 3/52 until disease progression or toxicity. Where available, assessment of BRAF mutation (V600E) was performed on historical tissue. Results: 14 pts have been enrolled, 3 were non-evaluable. Data are available for the first 11 pts (9 evaluable) completing accrual to the 1st stage of the Simon design. Demographics: 8 M/6 F; median age 55 years (range 30, 83). A total of 30 treatment cycles were administered (n=11); with relative dose intensity of 89%; 1 pt required a dose reduction. Grade 1–2 toxicity included nausea, vomiting, diarrhoea, anorexia, fatigue, headache, raised alkaline phosphatase/ALT/AST, and back pain. Four pts (29%) experienced Grade 3–4 toxicities: 1) reversible metabolic acidosis with LFT and electrolyte abnormalities; 2) anorexia, dehydration and fatigue; 3) raised gamma-GT; 4) abdominal pain. Two pts withdrew due to toxicity. Of the 4 pts with available tissue: 2 had V600E BRAF positive mutations. One pt achieved a ≥ 24 week PFS, meeting the conditions for accrual of Stage 2. This pt (with V600E mutation) was assessed as having a best response of stable disease as per RECIST, in addition to reduction in size and number of extensive subcutaneous nodules. Conclusions: There is evidence of clinical activity of single-agent tanespimycin in metastatic melanoma. Further accrual with determination of BRAF status to a total of 30 pts will better define the activity of tanespimycin in this population. No significant financial relationships to disclose.

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