Divergent Synthesis of a Pochonin Library Targeting HSP90 and In Vivo Efficacy of an Identified Inhibitor

Barluenga, Sofía; Wang, Cuihua; Fontaine, Jean-Gonzague; Aouadi, Kaïss; Beebe, Kristin; Tsutsumi, Shinji; Neckers, Len; Winssinger, Nicolas

doi:10.1002/anie.200800233

Cited by 56 publications

(25 citation statements)

References 34 publications

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“…In this study, we evaluated NXD30001, a novel HSP90 inhibitor based on the radicicol backbone, from NexGenix Pharmaceuticals (New York, NY, USA; Barluenga et al 2008Barluenga et al , 2009Wang et al 2009;Zhu et al 2010). We report that NXD30001 had a neuroprotective profile similar to geldanamycin in the ALS1 culture model, but with less toxicity.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

“…In plasma, NXD30001 cleared quickly and reached near the lower limit of quantitation level at 6 h. In contrast, NXD30001 levels in brain, spinal cord, liver, and muscle were still above the neuroprotective concentration used in culture (40 nM, equivalent to 20 ng/g of tissue) at 6 h, despite substantial decrease from levels at 1 h. Drug levels in liver and muscle were much higher than those in nervous tissues. To convert ng/g to molar concentration, multiply by 0.5 turnover of cell signaling molecules that are HSP90 client proteins (Barluenga et al 2008Wang et al 2009;Zhu et al 2010;Tanaka et al 2013).…”

Section: G93amentioning

confidence: 99%

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A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo

Jieun

Louis

Tradewell

et al. 2014

Cell Stress and Chaperones

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Heat shock proteins (HSPs) are attractive therapeutic targets for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), characterized by aberrant formation of protein aggregates. Although motor neurons have a high threshold for activation of HSP genes, HSP90 inhibitors are effective inducers. This study evaluated NXD30001, a novel, small molecule HSP90 inhibitor based on the radicicol backbone, for its ability to induce neuronal HSPs and for efficacy in an experimental model of ALS based on mutations in superoxide-dismutase 1 (SOD1). In motor neurons of dissociated murine spinal cord cultures, NXD30001-induced expression of HSP70/HSPA1 (iHSP70) and its co-chaperone HSP40/DNAJ through activation of HSF1 and exhibited a protective profile against SOD1 G93A similar to geldanamycin, but with less toxicity. Treatment prevented protein aggregation, mitochondrial fragmentation, and motor neuron death, important features of mutant SOD1 toxicity, but did not effectively prevent aberrant intracellular Ca 2+ accumulation. NXD30001 distributed to brain and spinal cord of wild-type and SOD1G93A transgenic mice following intraperitoneal injection; however, unlike in culture, in vivo levels of SOD1 were not reduced. NXD30001-induced expression of iHSP70 in skeletal and cardiac muscle and, to a lesser extent, in kidney, but not in liver, spinal cord, or brain, with either single or repeated administration. NXD30001 is a very useful experimental tool in culture, but these data point to the complex nature of HSP gene regulation in vivo and the necessity for early evaluation of the efficacy of novel HSP inducers in target tissues in vivo.

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Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Section: G93amentioning

confidence: 99%

A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo

Jieun

Louis

Tradewell

et al. 2014

Cell Stress and Chaperones

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“…Subsequent conditional deletion of Hsp90α, in adult mice, showed that the chaperone is essential for germ cell development in mature adult testes. 34 Extended exposure of pubertal male mice to high doses of the Hsp90α/β N-terminal domain inhibitor, pochoxime A, a new radicicol derivative with efficacy favorable for entry into brain and testes, 28,165,166 caused testicular atrophy in some of the animals similar to the phenotype seen in mice with genetic disruption of Hsp90α. 33 These results suggest that such drugs could be used to generate pharmacological infertility in male mice.…”

Section: Male Contraceptionmentioning

confidence: 99%

Hsp90 as a therapeutic target in endocrinology: current evidence

Ratajczak¹,

Ward²,

Walsh³

et al. 2015

RRED

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Abstract:The ability of heat shock protein 90 (Hsp90) to modulate many growth and signaling pathways simultaneously makes it an attractive target in the field of cancer therapeutics and provided the initial impetus for significant efforts over the past decade to identify Hsp90 inhibitors, several of which are now showing promise in the clinic for cancer treatment. The four known human Hsp90 members are compartmentalized: Hsp90α and β in the cytoplasm, GRP94 in the endoplasmic reticulum, and TRAP1 in the mitochondrial matrix. While these isoforms share a similar N-terminal domain adenosine triphosphate-binding pocket, structural variations allow unique interactions for inhibitors targeting this binding site, providing an avenue for the development of paralog-selective drugs with different biological effects applicable therapeutically to a wide range of diseases. At the same time, the conformational flexibility of the Hsp90 molecular chaperone has unveiled multiple small-molecule target sites within all subdomains of the protein, greatly expanding opportunities for viable drug development. This review summarizes the function, expression, and clinical significance of the Hsp90 isoforms and elaborates on the inhibitors and modulators that impact Hsp90 chaperone activity. Finally, the review focuses on the therapeutic utility of a range of Hsp90-modulating agents in the treatment of specific diseases associated with the endocrine system.

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“…The NPs pochonin D (6) and radicicol (7) were used as library template (8) by Winssinger's group (Fig. 7.13) [195]. This template was chosen to study the effect of structural modifications of pochonin on its activity on the heat-shock protein 90 (HSP90).…”

Section: Natural Products As Source Of Inspirationmentioning

confidence: 99%