Biotinylated Geldanamycin

Clevenger, Randell C.; Raibel, Joseph M.; Peck, Angela M.; Blagg, Brian S. J.

doi:10.1021/jo049848m

Cited by 24 publications

(18 citation statements)

References 40 publications

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“…17-Amino-derivatives 65 were prepared in the usual manner and the terminal amino group was then coupled with the biotin functionalised linker 66a or alternatively with the more hydrophilic PEG-derivatives 66b or 66c to yield conjugates 67 and 68, respectively (Scheme 15). 100 Biotinylated geldanamycin conjugates 69 and 70 containing photolabile linkers were also prepared in a similar fashion (Fig. 13).…”

Section: 95mentioning

confidence: 99%

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

et al. 2013

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In this review recent progress in the development of heat shock proteins (Hsp90) in oncogenesis is illuminated. Particular emphasis is put on inhibitors such as geldanamycin and analogues that serve as a natural product show case. Hsp90 has emerged as an important target in cancer therapy and/or against pathogenic cells which elicit abnormal Hsp patterns. Competition for ATP by geldanamycin and related compounds abrogate the chaperone function of Hsp90. In this context, this account pursues three topics in detail: a) Hsp90 and its biochemistry, b) Hsp90 and its role in oncogenesis and c) strategies to create compound libraries of structurally complex inhibitors like geldanamycin on which SAR studies and the development of drugs that are currently in different stages of clinical testing rely.

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Section: 95mentioning

confidence: 99%

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

et al. 2013

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“…Introduction of a diamino group at the 17-position of the quinone ring allowed subsequent coupling of the primary amine with biotin. These compounds were used to identify other proteins that bound bGDM [33]. In addition, bGDM was used by Kamal and coworkers in competitive binding assays to measure binding affinities of 17-AAG for immunoprecipitated Hsp90 heteroprotein complexes [31].…”

mentioning

confidence: 99%

“…In addition, bGDM was used by Kamal and coworkers in competitive binding assays to measure binding affinities of 17-AAG for immunoprecipitated Hsp90 heteroprotein complexes [31]. bGDM has also been used in fluorescence studies by researchers at the Genomics Institute of the Novartis Research Foundation, where a time-resolved fluorescence resonance energy transfer (FRET)-based high-throughput screening assay was developed to screen a library of 100,000 compounds [33]. Using this technique, these researchers identified several small molecules that exhibit binding affinities for Hsp90 in the high nanomolar range.…”

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confidence: 99%

Geldanamycin, Radicicol, and Chimeric Inhibitors of the Hsp90 Nterminal ATP Binding Site

Hadden¹,

Lubbers²,

Blagg³

2006

CTMC

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Natural products have continued to drive the development of new chemotherapeutics and elucidation of new biological targets for the treatment of disease. Since Whitesell and Neckers' original discovery that geldanamycin does not directly inhibit v-Src, but instead manifests its biological activity through inhibition of the Hsp90 molecular chaperone, additional natural products and natural product derivatives have been identified and developed to inhibit the Hsp90 protein folding machinery. 17-AAG, a geldanamycin analogue, is currently in clinical trials for the treatment of several types of cancer. Recent work has produced improved radicicol analogues that show promising Hsp90 inhibitory activity in vitro. In addition, chimeric molecules of these two natural products are active in vitro and represent a novel class of Hsp90 inhibitors for cancer treatment. In addition to their chemotherapeutic uses, natural product inhibitors and their derivatives have been utilized to probe the biological mechanisms by which Hsp90 inhibition regulates tumor cell growth. As a consequence of these studies, the molecular chaperones have emerged as an exciting new class of therapeutic targets. This review will highlight the utility of the natural products, geldanamycin and radicicol, as well as improved analogues and the activities exhibited by these compounds against various cancer cell lines.

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“…The azidophenyl derivative 9 labelled with 125 I has been used as a photoaffinity label to identify proteins which bind to geldanamycin [50]. A range of biotinylated geldanamycin derivatives has been prepared for use in the isolation of geldanamycin binding proteins using neutravidin resin [51]. These all involve linking the biotin via either a hydrophobic or a hydrophilic tether to a C-17 amino group and some also contain a photolabile group in the tether to enable the binding protein to be isolated.…”

Section: Geldanamycin Seriesmentioning

confidence: 99%

Inhibitors of the HSP90 Molecular Chaperone: Attacking the Master Regulator in Cancer

McDonald¹,

Workman²,

Jones³

2006

CTMC

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The heat shock protein 90 (HSP90) chaperones represent some 1-2% of all cellular protein and are key players in protein quality control in cells. They are over expressed in many human cancers and the fact that many oncogenic proteins are clients has prompted much recent research on HSP90 inhibitors as new cancer therapeutics. A brief introduction is followed by a detailed review of the various classes of inhibitors, both natural product-based and synthetic, that have emerged over the last decade. The natural products geldanamycin, radicicol and novobiocin have provided the start points for new drugs in this area and their medicinal chemistry is reviewed, including the exciting recent results emerging from clinical trials using geldanamycin analogues. The detailed understanding of the binding mode of these compounds to HSP90 has been significantly enhanced by X-ray crystallography of HSP90 constructs co-crystallised with various ligands. Efforts to replace the natural product inhibitors with more drug-like synthetic compounds have mushroomed over the last 4 years. The purines and the 3,4-diarylpyrazoles have proven to be the most successful and their medicinal chemistry is reviewed with particular emphasis on structure-based design. Protein/ligand co-crystal structures have shown that conserved water molecules in the active site are a vital part of the hydrogen-bonding network established on binding both natural product and synthetic inhibitors. Medicinal chemists have used this information to develop high affinity lead compounds. Recent research provides the platform for exciting developments in the area of HSP90 inhibition over the next few years.

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Biotinylated Geldanamycin

Cited by 24 publications

References 40 publications

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

Geldanamycin, Radicicol, and Chimeric Inhibitors of the Hsp90 Nterminal ATP Binding Site

Inhibitors of the HSP90 Molecular Chaperone: Attacking the Master Regulator in Cancer

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