Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors

Bhat, Rohit; Adam, Amna T.; Lee, Jungeun Jasmine; Gasiewicz, Thomas A.; Henry, Ellen C.; Rotella, David P.

doi:10.1016/j.bmcl.2014.03.088

Cited by 22 publications

(14 citation statements)

References 10 publications

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“…The studies described here may lay the foundation to evaluate structure-activity relationships for analogs of EGCG that have increased bioavailability, while inhibiting HSP90 function to elicit stronger anti-cancer properties with limited side effects (38). …”

Section: Discussionmentioning

confidence: 99%

The Heat Shock Protein 90 Inhibitor, (−)-Epigallocatechin Gallate, Has Anticancer Activity in a Novel Human Prostate Cancer Progression Model

Moses

Henry

Ricke

et al. 2015

Cancer Prevention Research

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(−)-Epigallocatechin gallate (EGCG), a major tea polyphenol, elicits anti-cancer effects. However, the mechanism of action is not fully understood. Our laboratory previously showed that EGCG inhibits heat shock protein 90 (HSP90). We utilized non-tumorigenic (NT), tumorigenic, and metastatic cancer cells from a novel human prostate cancer (PRCA) progression model to test the hypotheses that certain stages are more or less sensitive to EGCG and that sensitivity is related to HSP90 inhibition. Treatment of cells with EGCG, novobiocin (NB), or 17-AAG resulted in more potent cytotoxic effects on tumorigenic and metastatic cells than NT cells. When tumorigenic or metastatic cells were grown in vivo, mice supplemented with 0.06% EGCG in drinking water developed significantly smaller tumors than untreated mice. Furthermore, EGCG prevented malignant transformation in vivo using the full PRCA model. To elucidate the mechanism of EGCG action, we performed binding assays with EGCG-Sepharose, a C-terminal HSP90 antibody, and HSP90 mutants. These experiments revealed that EGCG-Sepharose bound more HSP90 from metastatic cells compared to NT cells and binding occurred through the HSP90 C-terminus. Additionally, EGCG bound HSP90 mutants that mimic both complexed and uncomplexed HSP90. Consistent with HSP90 inhibitory activity, EGCG, NB, and 17-AAG induced changes in HSP90-client proteins in NT cells and larger differences in metastatic cells. These data suggest that EGCG may be efficacious for the treatment of PRCA because it preferentially targets cancer cells and inhibits a molecular chaperone supportive of the malignant phenotype.

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Section: Discussionmentioning

confidence: 99%

The Heat Shock Protein 90 Inhibitor, (−)-Epigallocatechin Gallate, Has Anticancer Activity in a Novel Human Prostate Cancer Progression Model

Moses

Henry

Ricke

et al. 2015

Cancer Prevention Research

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“…Proteolytic footprinting and ATP-agarose pulldown assays demonstrated that 38 bound to Hsp90C without affecting the N-terminal ATP pocket . Structural modification of 38 resulted in analog 39 , which had improved antitumor activity of greater than 18-fold against MCF-7 cells . Additionally, derrubone ( 40 ) and silybin ( 42 ) were shown to possess antitumor activity related to targeting Hsp90C.…”

Section: Strategies For Hsp90 Inhibitionmentioning

confidence: 99%

Heat Shock Protein 90 Inhibitors: An Update on Achievements, Challenges, and Future Directions

et al. 2019

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Hsp90 is one of the most important chaperones involved in regulating the maturation of more than 300 client proteins, many of which are closely associated with refractory diseases, including cancer, neurodegenerative diseases, and viral infections. Clinical Hsp90 inhibitors bind to the ATP pocket in the N-terminal domain of Hsp90 and subsequently suppress the ATPase activity of Hsp90. Recently, with the increased understanding of the discrepancies in the isoforms of Hsp90 and the modes of Hsp90-co-chaperone-client complex interactions, some new strategies for Hsp90 inhibition have emerged. Novel Hsp90 inhibitors that offer selective suppression of Hsp90 isoforms or specific disruption of Hsp90-co-chaperone protein–protein interactions are expected to show with satisfactory efficacy and safety profiles. This review summarizes the recent progress in Hsp90 inhibitors. Additionally, Hsp90 inhibitory strategies are emphasized in this review.

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“…(2 R ,3 R )-5,7-Bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl cyclopropanecarboxylate ( 17a ) was obtained as a white solid [ 52 ]. A solution of 12 (0.07 mmol) and 4-DMAP (0.175 mmol) in CH 2 Cl 2 (4 mL) was added dropwisely to a solution of cyclopropanecarbonyl chloride (0.14 mmol) in CH 2 Cl 2 (1 mL) at 0 °C.…”

Section: Methodsmentioning

confidence: 99%

Ebola Entry Inhibitors Discovered from Maesa perlarius

Tsang

Varhegyi

et al. 2022

IJMS

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Ebola virus disease (EVD), a disease caused by infection with Ebola virus (EBOV), is characterized by hemorrhagic fever and a high case fatality rate. With limited options for the treatment of EVD, anti-Ebola viral therapeutics need to be urgently developed. In this study, over 500 extracts of medicinal plants collected in the Lingnan region were tested against infection with Ebola-virus-pseudotyped particles (EBOVpp), leading to the discovery of Maesa perlarius as an anti-EBOV plant lead. The methanol extract (MPBE) of the stems of this plant showed an inhibitory effect against EBOVpp, with an IC50 value of 0.52 µg/mL, which was confirmed by testing the extract against infectious EBOV in a biosafety level 4 laboratory. The bioassay-guided fractionation of MPBE resulted in three proanthocyanidins (procyanidin B2 (1), procyanidin C1 (2), and epicatechin-(4β→8)-epicatechin-(4β→8)-epicatechin-(4β→8)-epicatechin (3)), along with two flavan-3-ols ((+)-catechin (4) and (−)-epicatechin (5)). The IC50 values of the compounds against pseudovirion-bearing EBOV-GP ranged from 0.83 to 36.0 µM, with 1 as the most potent inhibitor. The anti-EBOV activities of five synthetic derivatives together with six commercially available analogues, including EGCG ((−)-epigallocatechin-3-O-gallate (8)), were further investigated. Molecular docking analysis and binding affinity measurement suggested the EBOV glycoprotein could be a potential molecular target for 1 and its related compounds.

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Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors

Cited by 22 publications

References 10 publications

The Heat Shock Protein 90 Inhibitor, (−)-Epigallocatechin Gallate, Has Anticancer Activity in a Novel Human Prostate Cancer Progression Model

The Heat Shock Protein 90 Inhibitor, (−)-Epigallocatechin Gallate, Has Anticancer Activity in a Novel Human Prostate Cancer Progression Model

Heat Shock Protein 90 Inhibitors: An Update on Achievements, Challenges, and Future Directions

Ebola Entry Inhibitors Discovered from Maesa perlarius

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