scholarly journals Using thrombocytopenia modeling to investigate the mechanisms underlying platelet depletion induced by pan‐proteasome inhibitors

2021 ◽  
Author(s):  
Floriane Lignet ◽  
Andreas D. Becker ◽  
Claude Gimmi ◽  
Felix Rohdich ◽  
Samer El Bawab
Keyword(s):  
Proteasome Inhibitors ◽  
Platelet Depletion

Proteasome inhibitors as therapeutics

2005 ◽  
Vol 41 ◽  
pp. 205-218
Author(s):  
Constantine S. Mitsiades ◽  
Nicholas Mitsiades ◽  
Teru Hideshima ◽  
Paul G. Richardson ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Drug Class ◽  
Proteasome Inhibitors ◽  
Cell Cycle Regulators ◽  
Current State ◽  
Intracellular Mechanism ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Hodgkin's Lymphomas ◽  
Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

Computer Modeling-Assisted Design And Synthesis Of Flavonols Derivatives As Proteasome Inhibitors

Planta Medica ◽  
2016 ◽  
Vol 82 (05) ◽  
Author(s):  
KY Orabi ◽  
MS Abaza ◽  
KA ElSayed ◽  
AY Elnagar ◽  
SI Faggal ◽  
...  
Keyword(s):  
Computer Modeling ◽  
Proteasome Inhibitors ◽  
Design And Synthesis

Synthesis of novel potential proteasome inhibitors based on tripeptide backbone

2013 ◽  
Author(s):  
Jan Dušek ◽  
Aleš Imramovský ◽  
Karel Pauk ◽  
Radek Jorda ◽  
Eva Řezníčková ◽  
...  
Keyword(s):  
Proteasome Inhibitors

Cascade CuH-Catalyzed Conversion of Alkynes to Enantioenriched 1,1-Disubstituted Products

2019 ◽  
Author(s):  
De-Wei Gao ◽  
Yang Gao ◽  
Huiling Shao ◽  
Tian-Zhang Qiao ◽  
Xin Wang ◽  
...  
Keyword(s):  
Organic Synthesis ◽  
Medicinal Chemistry ◽  
Proteasome Inhibitors ◽  
Building Blocks ◽  
Unique Role ◽  
Efficient Strategy ◽  
Carbon Centers ◽  
Rapid Access ◽  
Cascade Catalysis ◽  
Privileged Scaffolds

Enantioenriched <i>α</i>-aminoboronic acids play a unique role in medicinal chemistry and have emerged as privileged pharmacophores in proteasome inhibitors. Additionally, they represent synthetically useful chiral building blocks in organic synthesis. Recently, CuH-catalyzed asymmetric alkene hydrofunctionalization has become a powerful tool to construct stereogenic carbon centers. In contrast, applying CuH cascade catalysis to achieve reductive 1,1-difunctionalization of alkynes remains an important, but largely unaddressed, synthetic challenge. Herein, we report an efficient strategy to synthesize <i>α</i>-aminoboronates <i>via </i>CuH-catalyzed hydroboration/hydroamination cascade of readily available alkynes. Notably, this transformation selectively delivers the desired 1,1-heterodifunctionalized product in favor of alternative homodifunctionalized, 1,2-heterodifunctionalized, or reductively monofunctionalized byproducts, thereby offering rapid access to these privileged scaffolds with high chemo-, regio- and enantioselectivity.<br>

scholarly journals Platelet Depletion is Effective in Ameliorating Anxiety-Like Behavior and Reducing the Pro-Inflammatory Environment in the Hippocampus in Murine Experimental Autoimmune Encephalomyelitis

2019 ◽  
Vol 8 (2) ◽  
pp. 162 ◽  
Author(s):  
Pece Kocovski ◽  
Xiangrui Jiang ◽  
Claretta D’Souza ◽  
Zhenjiang Li ◽  
Phuc Dang ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Neuropsychiatric Symptoms ◽  
Critical Role ◽  
Clinical Manifestations ◽  
Lymphocytic Infiltration ◽  
Disease Stage ◽  
Autoimmune Encephalomyelitis ◽  
Significant Difference ◽  
Platelet Depletion ◽  
Experimental Autoimmune

The neuropsychiatric symptoms of multiple sclerosis (MS), such as anxiety and depression, can result from disease activity itself as well as psychological reaction to an unfavorable diagnosis. Accordingly, the literature reports evidence of increased anxiety-like behavior in experimental autoimmune encephalomyelitis (EAE), an accepted MS model. Due to the recently described critical role of platelets in inflammation and autoimmune disease, we examined the relationship between platelets, inflammation, and anxiety-like behavior in EAE. In the elevated plus maze, EAE-induced C57BL/6J mice showed decreased time spent in the open arms relative to vehicle-only controls, demonstrating an increase in anxiety-like behavior. This effect occurred in the presence of platelet–neuron association, but absence of lymphocytic infiltration, in the hippocampal parenchyma. Platelet depletion at the pre-clinical disease stage, using antibody-mediated lysis prevented the EAE-induced increase in anxiety-like behavior, while no significant difference in distance moved was recorded. Furthermore, platelet depletion was also associated with reduction of the pro-inflammatory environment to control levels in the hippocampus and prevention of EAE disease symptomology. These studies demonstrate the high efficacy of a platelet-targeting approach in preventing anxiety-like symptoms and clinical manifestations of EAE and have implications for the treatment of neuropsychiatric symptoms in MS.

scholarly journals Boosting Immunity against Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1221
Author(s):  
Raquel Lopes ◽  
Bruna Velosa Ferreira ◽  
Joana Caetano ◽  
Filipa Barahona ◽  
Emilie Arnault Carneiro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Proteasome Inhibitors ◽  
Treatment Strategies ◽  
Complete Response ◽  
Drug Conjugates ◽  
Incurable Disease ◽  
Car T ◽  
Patient’S Outcome ◽  
The Impact

Despite the improvement of patient’s outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody–drug conjugates or bispecific antibodies broadened the possibility of improving patients’ survival. However, thus far, these treatment strategies have not been able to steadily eliminate all malignant cells, and the aim has been to induce a long-term complete response with minimal residual disease (MRD)-negative status. In this sense, approaches that target not only myeloma cells but also the surrounding microenvironment are promising strategies to achieve a sustained MRD negativity with prolonged survival. This review provides an overview of current and future strategies used for immunomodulation of MM focusing on the impact on bone marrow (BM) immunome.

scholarly journals Stimulation of de novo glutathione synthesis by nitrofurantoin for enhanced resilience of hepatocytes

2021 ◽  
Author(s):  
Lukas S. Wijaya ◽  
Carina Rau ◽  
Theresa S. Braun ◽  
Serif Marangoz ◽  
Vincent Spegg ◽  
...  
Keyword(s):  
De Novo ◽  
Hepatoma Cell ◽  
Proteasome Inhibitors ◽  
Essential Element ◽  
Hepatoma Cell Line ◽  
Related Factor ◽  
Human Hepatoma Cell ◽  
Intact Cells ◽  
Intracellular Glutathione ◽  
Endogenous Antioxidant

AbstractToxicity is not only a function of damage mechanisms, but is also determined by cellular resilience factors. Glutathione has been reported as essential element to counteract negative influences. The present work hence pursued the question how intracellular glutathione can be elevated transiently to render cells more resistant toward harmful conditions. The antibiotic nitrofurantoin (NFT) was identified to stimulate de novo synthesis of glutathione in the human hepatoma cell line, HepG2, and in primary human hepatocytes. In intact cells, activation of NFT yielded a radical anion, which subsequently initiated nuclear-factor-erythroid 2-related-factor-2 (Nrf2)-dependent induction of glutamate cysteine ligase (GCL). Application of siRNA-based intervention approaches confirmed the involvement of the Nrf2-GCL axis in the observed elevation of intracellular glutathione levels. Quantitative activation of Nrf2 by NFT, and the subsequent rise in glutathione, were similar as observed with the potent experimental Nrf2 activator diethyl maleate. The elevation of glutathione levels, observed even 48 h after withdrawal of NFT, rendered cells resistant to different stressors such as the mitochondrial inhibitor rotenone, the redox cycler paraquat, the proteasome inhibitors MG-132 or bortezomib, or high concentrations of NFT. Repurpose of the antibiotic NFT as activator of Nrf2 could thus be a promising strategy for a transient and targeted activation of the endogenous antioxidant machinery.

scholarly journals Synthesis and Biochemical Evaluation of Warhead-Decorated Psoralens as (Immuno)Proteasome Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 356
Author(s):  
Eva Shannon Schiffrer ◽  
Matic Proj ◽  
Martina Gobec ◽  
Luka Rejc ◽  
Andrej Šterman ◽  
...  
Keyword(s):  
Chemical Space ◽  
Inflammatory Diseases ◽  
Proteasome Inhibitors ◽  
Selective Inhibition ◽  
Selective Inhibitors ◽  
Catalytic Activities ◽  
Elevated Expression ◽  
Crucial Information ◽  
Biochemical Evaluation ◽  
Viable Approach

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure–activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.

Sign in / Sign up

Export Citation Format

Share Document