Geldanamycin and its derivatives as Hsp90 inhibitors

Górska, M.; Popowska, Urszula; Sielicka-Dudzin, Alicja; Kuban–Jankowska, Alicja; Sawczuk, Wojciech; Knap, Narcyz; Cicero, Giuseppe; Wozniak, Fabio

doi:10.2741/4050

Cited by 69 publications

(47 citation statements)

References 65 publications

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“…10–12 N-terminal inhibitors have entered clinical studies for the treatment of various cancers. 13–15 However, some concerns have been raised that must be addressed before new Hsp90 inhibitors are developed.…”

Section: Introductionmentioning

confidence: 99%

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

et al. 2016

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Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure–activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.

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Section: Introductionmentioning

confidence: 99%

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

et al. 2016

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“…by up-regulating NF-κB [13,14]. As Hsp90 expression is particularly high in cancer cells and is associated with tumor cell progression, invasion and formation of metastases, as well as development of drug resistance [2], geldanamycin and its analogues have been considered for treament of cancer [2,3,12,15,16,17,18,19]. Geldanamycin has been shown to induce apoptosis [1,5,6,8,9,10,15,20,21,22,23], an effect paralleled by altered gene expression, downregulation of Akt, p38 MAPK activation, mitochondrial depolarization, reactive oxygen species formation, decline of reduced glutathion, lipid peroxidation and caspase activation [5,9,15,20,21].…”

Section: Introductionmentioning

confidence: 99%

“…The benzoquinone ansamycin antibiotic geldanamycin has been shown to inhibit heat shock protein Hsp90 [1,2,3,4,5,6,7,8,9,10,11,12], which prevents stress-induced cellular damage [2], stabilizes various oncogenic kinases [1,7,9,10,12] and influences gene expression e.g. by up-regulating NF-κB [13,14].…”

Section: Introductionmentioning

confidence: 99%

Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane

Jilani

Qadri

Läng

2013

Cell Physiol Biochem

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Background/aims: Geldanamycin, a benzoquinone ansamycin antibiotic, and its analogues induce apoptosis of tumor cells and are thus considered for the treatment of cancer. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine-exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca²⁺-concentration ([Ca²⁺]_i) and formation of ceramide. The present study explored, whether geldanamycin modifies [Ca²⁺]_i, ceramide formation, cell volume and phosphatidylserine abundance at the erythrocyte surface. Methods: Erythrocyte volume was estimated from forward scatter, phosphatidylserine-abundance from annexin V binding, hemolysis from hemoglobin release, ceramide formation from binding of fluorescent antibodies and [Ca²⁺]_i from Fluo3-fluorescence. Results: A 48 hours exposure to geldanamycin significantly decreased forward scatter (≥ 5 µM), significantly increased annexin-V-binding (≥ 25 µM), but did not significantly modify Fluo3-fluorescence (up to 50 µM). The annexin-V-binding following geldanamycin treatment was not significantly modified by removal of extracellular Ca²⁺ but was paralleled by significantly increased ceramide formation (50 µM). Conclusions: Geldanamycin stinulated eryptosis, an effect at least partially due to ceramide formation.

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“…We first verified that both whole body hyperthermia and geldanamycin, a benzoquinone ansamycin antibiotic that is a pharmacologic activator of the heat shock response 29 , cause a significant increase in the expression of the inducible heat shock protein Hsp72 in the mouse lung compared to controls without whole body hyperthermia or vehicle (fig. 1A and B).…”

Section: Resultsmentioning

confidence: 92%

Heat-shock Response Increases Lung Injury Caused byPseudomonas aeruginosa viaan Interleukin-10-dependent Mechanism in Mice

et al. 2014

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Background The heat shock response (HSR) protects from insults, such as ischemia-reperfusion injury, by inhibiting signaling pathways activated by sterile inflammation. However, the mechanisms by which the HSR activation would modulate lung damage and host response to a bacterial lung infection remain unknown. Methods HSR was activated with whole body hyperthermia or by intraperitoneal geldanamycin in mice that had their lungs instilled with Pseudomonas (P.) aeruginosa 24 h later (at least six mice per experimental group). Four hours after instillation, lung endothelial and epithelial permeability, bacterial counts, protein levels in bronchoalveolar lavage fluid and lung myeloperoxidase activity were measured. Mortality rate 24 h after P. aeruginosa instillation was recorded. The HSR effect on the release of interleukin (IL)-10 and killing of P. aeruginosa bacteria by a mouse alveolar macrophage cell line and on neutrophil phagocytosis was also examined. Results HSR activation worsened lung endothelial (42%) and epithelial permeability (50%) to protein, decreased lung bacterial clearance (71%) and increased mortality (50%) associated with P. aeruginosa pneumonia, an effect that was not observed in Hsp72 null mice. HSR-mediated decrease in neutrophil phagocytosis (69%) and bacterial killing (38%) by macrophages was IL-10-dependent, a mechanism confirmed by increased lung bacterial clearance and decreased mortality (70%) caused by P. aeruginosa pneumonia in heat-shocked IL-10 null mice. Conclusions Prior HSR activation worsens lung injury associated with P. aeruginosa pneumonia in mice via Hsp72 and IL-10-dependent mechanisms. These results provide a novel mechanism for the immunosuppression observed after severe trauma that is known to activate HSR in humans.

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Geldanamycin and its derivatives as Hsp90 inhibitors

Cited by 69 publications

References 65 publications

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane

Heat-shock Response Increases Lung Injury Caused byPseudomonas aeruginosa viaan Interleukin-10-dependent Mechanism in Mice

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