Immunoproteasome-selective and non-selective inhibitors: A promising approach for the treatment of multiple myeloma

Ettari, Roberta; Zappalà, Maria; Grasso, Silvana; Musolino, Caterina; Innao, Vanessa; Allegra, Alessandro

doi:10.1016/j.pharmthera.2017.09.001

Cited by 81 publications

(85 citation statements)

References 153 publications

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“…Thus, targeting immunoproteasomes could be av aluable strategy for the treatment of this hematologic malignancy. [9][10][11] In this context, several b5i and/or b1i immunoproteasome-selective inhibitors have been identified. [12][13][14] Furthermore,i nr ecent years, noncovalent proteasome/immunoproteasomei nhibitors have been generated, thus providing important insighti nto the basic concepts of noncovalent proteasome inhibitor design.…”

Section: Introductionmentioning

confidence: 99%

Development of Novel Amides as Noncovalent Inhibitors of Immunoproteasomes

et al. 2019

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The development of immunoproteasome‐selective inhibitors is a promising strategy for treating hematologic malignancies, autoimmune and inflammatory diseases. In this context, we report the design, synthesis, and biological evaluation of a new series of amide derivatives as immunoproteasome inhibitors. Notably, the designed compounds act as noncovalent inhibitors, which might be a promising therapeutic option because of the lack of drawbacks and side effects associated with irreversible inhibition. Among the synthesized compounds, we identified a panel of active inhibitors with Ki values in the low micromolar or sub‐micromolar ranges toward the β5i and/or β1i subunits of immunoproteasomes. One of the active compounds was shown to be the most potent and selective inhibitor with a Ki value of 21 nm against the single β1i subunit. Docking studies allowed us to determine the mode of binding of the molecules in the catalytic site of immunoproteasome subunits.

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Section: Introductionmentioning

confidence: 99%

Development of Novel Amides as Noncovalent Inhibitors of Immunoproteasomes

et al. 2019

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“…Therefore, considerable efforts have been made for developing immunoproteasome-specific inhibitors that could be used as therapeutic agents for the treatment of autoimmune disorders. 86 ONX-0914 ( Figure 12) was the first selective epoxyketone-based peptidyl immunoproteasome inhibitor, which showed potent inhibitory activity for β5i and moderated activity against β5c with IC 50 values of 5.7 nM and 54 nM, respectively. In addition, it also displayed moderate inhibitory activities against β1i (IC 50 : 460 nM) and β2i (IC 50 : 590 nM).…”

Section: Immunologic and Autoimmune Diseasesmentioning

confidence: 99%

<p>Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer</p>

Cao¹,

Zhu²,

He³

et al. 2020

DDDT

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Proteasome is vital for intracellular protein homeostasis as it eliminates misfolded and damaged protein. Inhibition of proteasome has been validated as a powerful strategy for anti-cancer therapy, and several drugs have been approved for treatment of multiple myeloma. Recent studies indicate that proteasome has potent therapeutic effects on a variety of diseases besides cancer, including parasite infectious diseases, bacterial/fungal infections diseases, neurodegenerative diseases and autoimmune diseases. In this review, recent developments of proteasome inhibitors for various diseases and related structure activity relationships are going to be summarized.

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“…Other milestones in MM treatments are PIs [123]. Mitra et al [126] analyzed the drug response of individual cells based on target transcriptome in pretreatment cell analysis, thus predicting PIs-resistance, i.e., the residual resistance affected the PItreatment response [126].…”

Section: Proteasome Inhibitors (Pis)mentioning

confidence: 99%

High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

Solimando¹,

Viá²,

Cicco³

et al. 2019

Preprint

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Multiple myeloma (MM) is a genetically heterogenous disease that includes a subgroup of 10-15% of patients facing dismal survival despite most intensive treatment. The aim of this review article is to provide an integrated clinical and biological overview on the high-risk MM discussing the novel therapeutic perspectives aimed to target the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug resistance can foster a better tailored clinical management of high-risk profile and refractoriness to therapy. Among the current clinical difficulties in MM, patient’s management manipulating the tumor niche represents a major challenge given the limited knowledge about the MM-milieu interaction. The angiogenesis and bystander infiltrate constitute pivotal mechanisms of mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy but variable and unpredictable responses in high-risk MM. Therefore, it would be worth to better select the population and the MM stage that could profit to a dual immune/vasculogenesis targeting. The comprehensive knowledge of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Despite significant improvements in the biology knowledge, MM is still a chronic and incurable neoplasia and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. Here, we corroborate previous biological findings providing a synthetic outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better personalize the patient-oriented clinical management.

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Immunoproteasome-selective and non-selective inhibitors: A promising approach for the treatment of multiple myeloma

Cited by 81 publications

References 153 publications

Development of Novel Amides as Noncovalent Inhibitors of Immunoproteasomes

Development of Novel Amides as Noncovalent Inhibitors of Immunoproteasomes

<p>Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer</p>

High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

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