Following the design path of isoform-selective Hsp90 inhibitors: Small differences, great opportunities

Dernovšek, Jaka; Tomašič, Tihomir

doi:10.1016/j.pharmthera.2023.108396

Cited by 17 publications

(6 citation statements)

References 142 publications

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“…To date, no HSP90 inhibitor has been approved for cancer therapeutics. The primary obstacles preventing the clinical application of HSP90 inhibitors are the lack of drug-like properties, organ toxicity, and drug resistance (Dernovšek & Tomašič, 2023). In this study, in vivo experiments showed that PPP exerts no toxicity on the primary organs of mice, thereby suggesting its potential as a natural and safe inhibitor of HSP90.…”

Section: Discussionmentioning

confidence: 58%

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT

Wang

Zhou

et al. 2023

Phytotherapy Research

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Gastric cancer (GC) is one of the most common malignant tumors worldwide. Thus, the development of safe and effective therapeutic compounds for GC treatment is urgently required. Here, we aimed to examine the role of picropodophyllin (PPP), a compound extracted from the rhizome of Dysosma versipellis (Hance) M. Cheng ex Ying, on the proliferation of GC cells. Our study revealed that PPP inhibits the proliferation of GC cells in a dose‐dependent manner by inducing apoptosis. Moreover, our study elucidated that PPP suppresses the growth of GC tumor xenografts with no side effects of observable toxicity. Mechanistically, PPP exerts its effects by blocking the AKT/mammalian target of rapamycin (mTOR) signaling pathway; these effects are markedly abrogated by the overexpression of constitutively active AKT. Furthermore, drug affinity responsive target stability (DARTS) and liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS) revealed that heat shock protein 90 (HSP90) may be a potential target of PPP. Surface plasmon resonance and immunoprecipitation assay validated that PPP directly targets HSP90 and disrupts the binding of HSP90 to AKT, thereby suppressing GC cell proliferation. Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment.

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Section: Discussionmentioning

confidence: 58%

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT

Wang

Zhou

et al. 2023

Phytotherapy Research

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“…Meanwhile, the synthesis and exploration of new Hsp90 drugs are also ongoing, as explained in the reviews by Dernovšek et al. ( 19 ) and Xie et al. ( 85 ).…”

Section: Discussionmentioning

confidence: 99%

“…There are also certain inhibitors for each domain. ATP-competitive inhibitors targets NTD, Hsp90-client protein and Hsp90-co-chaperone PPI inhibitors targets MD, while allosteric Hsp90 CTD inhibitors targets CTD ( 19 ).…”

Section: The Structure and Function Mechanisms Of Mthsp90mentioning

confidence: 99%

The development of cancers research based on mitochondrial heat shock protein 90

Xiang,

Liu,

Sun

et al. 2023

Front. Oncol.

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Mitochondrial heat shock protein 90 (mtHsp90), including Tumor necrosis factor receptor-associated protein 1 (TRAP1) and Hsp90 translocated from cytoplasm, modulating cellular metabolism and signaling pathways by altering the conformation, activity, and stability of numerous client proteins, and is highly expressed in tumors. mtHsp90 inhibition results in the destabilization and eventual degradation of its client proteins, leading to interference with various tumor-related pathways and efficient control of cancer cell development. Among these compounds, gamitrinib, a specific mtHsp90 inhibitor, has demonstrated its safety and efficacy in several preclinical investigations and is currently undergoing evaluation in clinical trials. This review aims to provide a comprehensive overview of the present knowledge pertaining to mtHsp90, encompassing its structure and function. Moreover, our main emphasis is on the development of mtHsp90 inhibitors for various cancer therapies, to present a thorough overview of the recent pre-clinical and clinical advancements in this field.

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“…5 PU-WS13 is another purine-based selective inhibitor of GRP94 (Figure 2K) with significant activity in breast cancer cells and multiple myeloma. 27,28 The synthetic purine-based inhibitor BIIB021 (Figure 2L) is an NTD-binding inhibitor of HSP90 with potent growth-inhibitory activity in cancer cells. Significant anti-cancer activity and good safety profiles were also demonstrated in phase I/II clinical studies.…”

Section: Purine and Pyrimidine Compoundsmentioning

confidence: 99%

Natural and Synthetic Inhibitors of Heat Shock Protein 90 Chaperone in Cancer Treatment

Ravula,

Akula,

Kancha

2024

Ind. J. Pharm. Edu. Res

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The heat shock protein 90 (HSP90) plays a crucial role in regulating cellular homeostasis. Importantly, enhanced dependence of cancer-specific proteins or mutants on HSP90 for their stability and activity offers HSP90 as an attractive therapeutic target. But, HSP90 being an important house-keeping protein, raised skepticism towards achieving cancer-specific therapeutic efficacy. Biochemical and functional studies revealed differential activity of HSP90 between healthy and cancer cells indicating the promise of specific chemical inhibitors in treating the disease. The current educational article elaborates on multiple classes of inhibitors that either have pre-clinical activity or being tested in various phases of clinical trials. In addition, recent pre-clinical findings that offer mechanistic insights into the therapeutic efficacy of HSP90 inhibitors are detailed. Thus, the article focuses on the promise of HSP90 as a therapeutic target and recent advances in the development of novel HSP90 inhibitors. Furthermore, we discuss the genetic factors and molecular mechanisms that influence the success of targeting HSP90 chaperone in cancer treatment.

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Following the design path of isoform-selective Hsp90 inhibitors: Small differences, great opportunities

Cited by 17 publications

References 142 publications

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT

The development of cancers research based on mitochondrial heat shock protein 90

Natural and Synthetic Inhibitors of Heat Shock Protein 90 Chaperone in Cancer Treatment

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