Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives

Keum, Gyochang; Pae, Ae Nim

doi:10.1517/13543776.2013.780597

Cited by 46 publications

(42 citation statements)

References 47 publications

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“…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%

“…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%

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane

Jilani

Qadri

Läng

2013

Cell Physiol Biochem

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“…75 Despite the tendency for such electronrich hydroquinones towards rapid oxidation back to the corresponding quinone, it appears that the formation of the salt (hydrochloride in the case of IPI-504) stabilises the reduced form, although an in-depth study of this has, to the best of our knowledge, yet to be reported. The aqueous solubility of benzoquinone ansamycins increases significantly upon reduction to the hydroquinone (1-3 mg mL À1 for 17-AAG hydroquinone vs. 35 mg mL À1 for 17-AAG) 91 and this is even more marked upon salt formation, with solubilities in excess of 200 mg mL À1 typical for salts of 17-AAG hydroquinone. 91 Despite its discontinuation for the treatment of refractory gastrointestinal stromal tumours following a high mortality rate of patients in a clinical trial, 91 retaspimycin continues to perform in the clinic, with accumulating evidence of efficacy against multiple myeloma, lung cancer, and other solid tumours.…”

Section: -Allylamino-17-desmethoxygeldanamycinmentioning

confidence: 99%

“…91 Despite its discontinuation for the treatment of refractory gastrointestinal stromal tumours following a high mortality rate of patients in a clinical trial, 91 retaspimycin continues to perform in the clinic, with accumulating evidence of efficacy against multiple myeloma, lung cancer, and other solid tumours. 91 In addition to retaspimycin, other non-quinone-based Hsp90 inhibitors have been discovered through biosynthetic engineering and can exhibit increased binding affinities compared to geldanamycin and macbecin, although oxidation to the quinone is still a potential source of toxicity for the analogues. 92…”

Section: -Allylamino-17-desmethoxygeldanamycinmentioning

confidence: 99%

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Recent Advances in Macrocyclic Hsp90 Inhibitors

Ramsey

Kitson

Levin

et al. 2014

Macrocycles in Drug Discovery

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Natural products were the first compounds to confirm the advantages of cyclised structures, where the ring conformation provides structural stability and chemical potency. Successful clinical applications of macrocyclic compounds in oncology have produced powerful incentives within the medicinal chemistry community to explore macrocyclic drug candidates that target novel oncogenic pathways. Numerous receptors, signalling molecules, and enzymes involved in oncogenesis require the chaperone activity of heat shock protein 90 (Hsp90), an ATPase-driven dimer whose chief molecular roles involve protein folding and stabilisation. Herein we describe four classes of macrocyclic Hsp90 inhibitors. Class I macrocyclic anticancer agents, currently in clinical trials, target the ATP-binding pocket of Hsp90 and include synthetic derivatives of the ansamycin antibiotic geldanamycin (17-AAG or tanespimycin, 17-DMAG or alvespimycin, IPI-504 or retaspimycin). Class II inhibitors (radicicol, radanamycin), which also target the ATP-binding pocket of Hsp90, demonstrate greater potency than Class I inhibitors in preclinical studies, and recent improvements incorporated into synthetic derivatives and chimeras have led to greater structural stability than class I without loss of potency. Class III features synthetic derivatives targeting Hsp90's ATPase activity (o-aminobenzamides and aminopyrimidines), with promising clinical data pointing to these scaffolds as the next generation of therapeutic Hsp90 inhibitors. Class IV compounds are allosteric inhibitors that bind to the N-middle domain of Hsp90 and block access to proteins that bind the C-terminus of Hsp90 (SM122 and SM145). This final class is unique as it does not target the ATP binding site of Hsp90, thereby avoiding induction of the heat shock response. Development of compounds that modulate Hsp90's C-terminus may prove to be an effective method of avoiding the rescue response mounted when blocking the ATP-ase activity of Hsp90.

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Combination of traditional mutation and metabolic engineering to enhance ansamitocin P‐3 production in Actinosynnema pretiosum

Zhang

Qian

et al. 2017

Biotech & Bioengineering

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Ansamitocin P-3 (AP-3) is a maytansinoid with its most compelling antitumor activity, however, the low production titer of AP-3 greatly restricts its wide commercial application. In this work, a combinatorial approach including random mutation and metabolic engineering was conducted to enhance AP-3 biosynthesis in Actinosynnema pretiosum. First, a mutant strain M was isolated by N-methyl-N'-nitro-N-nitrosoguanidine mutation, which could produce AP-3 almost threefold that of wild type (WT) in 48 deep-well plates. Then, by overexpressing key biosynthetic genes asmUdpg and asm13-17 in the M strain, a further 60% increase of AP-3 production in 250-ml shake flasks was achieved in the engineered strain M-asmUdpg:asm13-17 compared to the M strain, and its maximum AP-3 production reached 582.7 mg/L, which is the highest as ever reported. Both the gene transcription levels and intracellular intermediate concentrations in AP-3 biosynthesis pathway were significantly increased in the M and M-asmUdpg:asm13-17 during fermentation compared to the WT. The good fermentation performance of the engineered strain was also confirmed in a lab-scale bioreactor. This work demonstrated that combination of random mutation and metabolic engineering could promote AP-3 biosynthesis and might be helpful for increasing the production of other industrially important secondary metabolites.

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Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives

Cited by 46 publications

References 47 publications

Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane

Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane

Recent Advances in Macrocyclic Hsp90 Inhibitors

Combination of traditional mutation and metabolic engineering to enhance ansamitocin P‐3 production in Actinosynnema pretiosum

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