Bortezomib – First Therapeutic Proteasome Inhibitor for Cancer Therapy: A Review of Patent Literature

Vora, Pratik Ashwinbhai; Patel, Rakesh; Dharamsi, Abhay

doi:10.2174/1574892815666200401113805

Cited by 14 publications

(12 citation statements)

References 3 publications

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“…Virtually all of our compound 1-resistant clones, with the exception of RES IV (2.5-fold resistant), demonstrated considerable cross-resistance to this established proteasome inhibitor (20- to 127-fold; Table 2 ). In addition, the broad-spectrum anti-kinetoplastid proteasome inhibitor GNF6702 ( 20 ) demonstrated similar levels of cross-resistance against RES I to V clones, while there was no evidence of cross-resistance to the classical proteasome inhibitor bortezomib, used in the treatment of multiple myeloma, mantle cell lymphoma, and a number of other cancers ( 23 ) ( Table 2 ). GNF6702, GSK3494245, and analogues are known to target the same allosteric binding site at the interface of the β4/β5 subunits of the proteasome resulting in the inhibition of chymotrypsin-like activity.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Proteasome-Targeting Arylsulfonamide with Potential for the Treatment of Chagas’ Disease

Lima

Tulloch

Corpas‐López

et al. 2022

Antimicrob Agents Chemother

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Phenotypic screening identified an arylsulfonamide compound with activity against Trypanosoma cruzi , the causative agent of Chagas’ disease. Comprehensive mode of action studies revealed that this compound primarily targets the T. cruzi proteasome, binding at the interface between β4 and β5 subunits that catalyse chymotrypsin-like activity. A mutation in the β5 subunit of the proteasome was associated with resistance to compound 1 , while overexpression of this mutated subunit also reduced susceptibility to compound 1 . Further genetically engineered and in vitro selected clones resistant to proteasome inhibitors known to bind at the β4/β5 interface were cross-resistant to compound 1 . Ubiquitinylated proteins were additionally found to accumulate in compound 1 -treated epimastigotes. Finally, thermal proteome profiling identified malic enzyme as a secondary target of compound 1 , although malic enzyme inhibition was not found to drive potency. These studies identify a novel pharmacophore capable of inhibiting the T. cruzi proteasome that may be exploitable for anti-chagasic drug discovery.

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Section: Resultsmentioning

confidence: 99%

Identification of a Proteasome-Targeting Arylsulfonamide with Potential for the Treatment of Chagas’ Disease

Lima

Tulloch

Corpas‐López

et al. 2022

Antimicrob Agents Chemother

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“…Nelarabine is an effective anticancer chemotherapy prodrug of arabinfuranosylguanine triphosphate, that appears to meditate DNA degradation and cell death ( Robak et al, 2006 ). Similarly, midostaurin ( Hsiao et al, 2019 ), fluphenazine ( Otręba and Kośmider, 2021 ), bortezomib ( Vora et al, 2020 ), and vincristine ( Xu and Xu, 2020 ) also possess anticancer activity. The present findings revealed that GSDM gene expression may provide important guidance for the selection of targeted drugs for the treatment of cancer.…”

Section: Discussionmentioning

confidence: 99%

A systematic pan-cancer analysis of the gasdermin (GSDM) family of genes and their correlation with prognosis, the tumor microenvironment, and drug sensitivity

et al. 2022

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Background: Pyroptosis is a programmed cell death process mediated by the gasdermin (GSDM) protein. However, limited research has been conducted to comprehensively analyze the contribution of the GSDM family in a pan-cancer setting.Methods: We systematically evaluated the gene expression, genetic variations, and prognostic values of the GSDM family members. Furthermore, we investigated the association between the expression of GSDM genes and immune subtypes, the tumor microenvironment (TME), the stemness index, and cancer drug sensitivities by means of a pan-cancer analysis.Results: GSDM genes were highly upregulated in most of the tested cancers. Low-level mutation frequencies within GSDM genes were common across the examined types of cancer, and their expression levels were associated with prognosis, clinical characteristics, TME features, and stemness scores in several cancer types, particularly those of the urinary system. Importantly, we found that the expressions of GSDMB, GSDMC, and GSDMD were higher in kidney carcinomas, and specifically kidney renal clear cell carcinoma (KIRC); which adversely impacted the patient outcome. We showed that GSDMD was potentially the most useful biomarker for KIRC. The drug sensitivity analysis demonstrated that the expressions of GSDM genes were correlated with the sensitivity of tumor cells to treatment with chemotherapy drugs nelarabine, fluphenazine, dexrazoxane, bortezomib, midostaurin, and vincristine.Conclusion: GSDM genes were associated with tumor behaviors and may participate in carcinogenesis. The results of this study may therefore provide new directions for further investigating the role of GSDM genes as therapeutic targets in a pan-cancer setting.

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“…Currently, there has been much interest regarding the use of BZB, an original PI for other cancers therapy, such as rhabdomyosarcoma, HCC, malignant lymphoma, Hodgkin lymphoma, multiform glioblastoma, pancreatic cancer, bladder cancer, prostatic carcinoma, oophoroma, oesophageal cancer and leukaemia. The underlying mechanisms include inhibition of oncoproteins and induction of apoptosis, arrest of the cell cycle, suppression of EMT, reduction of stemness, stimulation of NK cell‐mediated immune response and inhibition of NF‐kappaB 22 . These mechanisms are somewhat dependent on its conventional proteasome inhibition.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib inhibits hepatocellular carcinoma via the Hippo‐Yes‐associated protein signalling pathway

Liao

Liu

et al. 2023

Basic Clin Pharma Tox

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Hepatocellular carcinoma (HCC) is one of the principle causes of cancer‐associated death throughout the world. However, the patients with HCC are insensitive to traditional drugs and lack effective therapeutic drugs. Dysregulation of Hippo‐Yes‐associated protein (YAP) signalling is closely associated with HCC. Bortezomib (BTZ) is mainly used in clinical multiple myeloma. It has recently been confirmed that BTZ could suppress cell proliferation in many different types of cancer. Nevertheless, the precise effects of BTZ on HCC and its possible interactions with the Hippo‐YAP signalling pathway in HCC cells remain largely unknown. In this study, HCC cell lines (HepG2 and Huh7) and nude mice with xenograft tumours were used to evaluate the influences of BTZ. Furthermore, we focused on exploring whether BTZ exerts its anti‐HCC effect through the Hippo‐YAP signalling pathway and aimed to lay a theoretical foundation for BTZ as a potential therapeutic drug for HCC. Herein, our results disclose a new mechanism of BTZ in controlling the cell growth of HCC. BTZ downregulates the level of YAP by promoting LATS1 expression to inhibit the growth of HCC cells, which leads to the phosphorylation of YAP and limits YAP nuclear translocation. In sum, our data confirmed that the Hippo‐YAP signalling pathway mediates the anti‐HCC effects of BTZ.

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Bortezomib – First Therapeutic Proteasome Inhibitor for Cancer Therapy: A Review of Patent Literature

Cited by 14 publications

References 3 publications

Identification of a Proteasome-Targeting Arylsulfonamide with Potential for the Treatment of Chagas’ Disease

Identification of a Proteasome-Targeting Arylsulfonamide with Potential for the Treatment of Chagas’ Disease

A systematic pan-cancer analysis of the gasdermin (GSDM) family of genes and their correlation with prognosis, the tumor microenvironment, and drug sensitivity

Bortezomib inhibits hepatocellular carcinoma via the Hippo‐Yes‐associated protein signalling pathway

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