Heat Shock Protein (HSP) Drug Discovery and Development: Targeting Heat Shock Proteins in Disease

Shrestha, Liza; Bolaender, Alexander; Patel, Hardik J.; Taldone, Tony

doi:10.2174/1568026616666160413141911

Cited by 90 publications

(64 citation statements)

References 93 publications

(114 reference statements)

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“…Hsp90, a family member of heat shock chaperone proteins, is a core protein of chaperone machinery and plays a critical role in the conformational stabilization of many mutant onco-proteins [77, 78]. Hsp90 is frequently overexpressed in many human tumors [77, 78]. Hsp90 can interact with mutant p53 to inhibit the ubiquitination and degradation of mutant p53 [79-82] (Figure 2).…”

Section: Mutant P53 Protein Accumulation In Tumorsmentioning

confidence: 99%

Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy

Yue

Zhao

et al. 2017

Journal of Molecular Biology

248

213

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Tumor suppressor p53 plays a central role in tumor suppression. p53 is the most frequently mutated gene in human cancer, and over half of human cancers contain p53 mutations. Majority of p53 mutations in cancer are missense mutations, leading to the expression of full-length mutant p53 protein. While the critical role of wild type p53 in tumor suppression has been firmly established, mounting evidence has demonstrated that many tumor-associated mutant p53 proteins not only lose tumor suppressive function of wild type p53, but also gain new activities to promote tumorigenesis independently of wild type p53, termed gain-of-function. Mutant p53 protein often accumulates to very high levels in tumors, contributing to malignant progression. Recently, mutant p53 has become an attractive target for cancer therapy. Further understanding of the mechanisms underlying mutant p53 protein accumulation and gain-of-function will accelerate the development of targeted therapies for human cancer harboring mutant p53. In this review, we summarize the recent advances in the studies on mutant p53 protein accumulation and gain-of-function as well as targeted therapies for mutant p53 in human cancer.

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Section: Mutant P53 Protein Accumulation In Tumorsmentioning

confidence: 99%

Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy

Yue

Zhao

et al. 2017

Journal of Molecular Biology

248

213

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“…Additionally, cellular signalling molecules IL‐8 and NF‐κB, early initiators of granulocyte recruitment, were inhibited by DMAG‐90 and exhibited a corresponding reduction in inflammatory cellular infiltrates in BP models . Clinical trials evaluating Hsp90 inhibition to date have been largely concerned with their utility as anti‐cancer agents . Evidence of focally increased expression of Hsp90 in BP lesions and amelioration of disease severity through Hsp90 inhibition in EBA mouse models should however provide optimism for therapeutic translation of Hsp90 inhibitors to the treatment of AIBD …”

Section: Evolving Therapeutic Targetsmentioning

confidence: 99%

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

Kridin

Kowalski

Kneiber

et al. 2019

Acad Dermatol Venereol

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Autoimmune blistering diseases comprise a group of heterogenous conditions characterized by the loss of tolerance and subsequent development of autoantibodies targeting epidermal and subepidermal adhesion proteins. Blisters and erosions form on the skin and mucous membranes leading to significant morbidity and mortality. Traditional therapies rely on systemic immunosuppression. Advancements in our understanding of the pathophysiology of pemphigus and pemphigoid have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. In this review, we outline the novel therapeutic strategies including B‐cell depletion, T‐regulatory cell repletion, cell signalling inhibitors and small molecular inhibitors, inhibitory monoclonal antibodies, as well as complement inhibition. We additionally review their current level of clinical evidence. We lastly review therapeutics targets gleaned from the experimental epidermolysis bullosa acquisita mouse model. These emerging treatments offer an exciting progression from basic science discoveries that have the potential to transform the treatment paradigm in autoimmune blistering diseases.

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“…Heat shock protein 90 (Hsp90), an ATP‐dependent molecular chaperone, facilitates the activation and stabilization of proteins (clients) that regulate various cellular processes . It forms the chaperone machinery with cochaperones for the maturation of Hsp90 clients, including receptor tyrosine kinases, signaling molecules, and cell cycle regulators. In addition to cochaperone association, ATP binding and hydrolysis, posttranslational modifications including phosphorylation, S‐nitrosylation, ethylation, and acetylation also regulate Hsp90 function .…”

Section: Introductionmentioning

confidence: 99%

“…Because Hsp90 clients are frequently mutated, overexpressed, or persistently activated in tumors, cancer cells use the Hsp90 chaperone machinery to protect clients from misfolding and degradation. Although many Hsp90 inhibitors are tested as anticancer agents in clinical trials, none of them have been approved due to side‐effects or lacking anticancer activity by upregulating other HSPs (eg, Hsp27 and Hsp72).…”

Section: Introductionmentioning

confidence: 99%

Simvastatin functions as a heat shock protein 90 inhibitor against triple‐negative breast cancer

et al. 2018

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Acetylation plays an important role in regulating the chaperone activity of heat shock protein 90 (Hsp90) during malignant transformation through the stabilization and conformational maturation of oncogenic proteins. However, the functional acetylation sites, potential anticancer drug targets, are still emerging. We found that acetylation at K292 in Hsp90α is critical for the development and treatment of breast cancer. Acetylation at K292 not only augments the affinity of Hsp90 to ATP, cochaperones, and client proteins but it also promotes cancer cell colony formation, migration, and invasion in vitro as well as tumor growth in vivo. Importantly, K292‐acetylated Hsp90 has been validated as an exciting anticancer drug target by interfering with the complex formation between K292‐acetylated Hsp90 and cochaperone Cdc37, leading to diminishment of kinase client maturation and proteasome‐dependent degradation of kinase substrates. Furthermore, we showed that simvastatin prevented, whereas LBH589 promoted, the progression of Hsp90 chaperone cycling and client maturation, resulting in an increment of cell apoptosis by the combination of simvastatin and LBH589 in a mouse xenograft model. These data suggest that simvastatin is a novel Hsp90 inhibitor to disrupt the formation of the K292‐acetylated Hsp90/Cdc37 complex in triple‐negative breast cancer cells. The combination of simvastatin with LBH589 could be used as a novel therapeutic strategy for triple‐negative breast cancer.

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Heat Shock Protein (HSP) Drug Discovery and Development: Targeting Heat Shock Proteins in Disease

Cited by 90 publications

References 93 publications

Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy

Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

Simvastatin functions as a heat shock protein 90 inhibitor against triple‐negative breast cancer

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