Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib

2018 ◽  
Vol 28 (12) ◽  
pp. 2148-2152 ◽  
Author(s):  
Yulong Xu ◽  
Xicheng Yang ◽  
Yiyi Chen ◽  
Hao Chen ◽  
Huijiao Sun ◽  
...  
Keyword(s):  
Proteasome Inhibitors ◽  
20S Proteasome ◽  
Scaffold Hopping

Convergent Synthesis and Biological Evaluation of Syringolin A and Derivatives as Eukaryotic 20S Proteasome Inhibitors

2010 ◽  
Vol 2010 (21) ◽  
pp. 3991-4003 ◽  
Author(s):  
Jérôme Clerc ◽  
Barbara Schellenberg ◽  
Michael Groll ◽  
André S. Bachmann ◽  
Robert Huber ◽  
...  
Keyword(s):  
Proteasome Inhibitors ◽  
Biological Evaluation ◽  
20S Proteasome ◽  
Convergent Synthesis ◽  
Synthesis And Biological Evaluation

scholarly journals Sequence analysis of β-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4513-4516 ◽  
Author(s):  
David I. Lichter ◽  
Hadi Danaee ◽  
Michael D. Pickard ◽  
Olga Tayber ◽  
Michael Sintchak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Nucleotide Polymorphism ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Allelic Frequency ◽  
High Dose ◽  
20S Proteasome ◽  
Clinical Relapse ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide

AbstractVariations within proteasome β (PSMB) genes, which encode the β subunits of the 20S proteasome, may affect proteasome function, assembly, and/or binding of proteasome inhibitors. To investigate the potential association between PSMB gene variants and treatment-emergent resistance to bortezomib and/or long-term outcomes, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity. This study is registered at www.clinicaltrials.gov as NCT00048230.

Synthesis of Salinosporamide A and Its Analogs as 20S Proteasome Inhibitors and SAR Summarization

2011 ◽  
Vol 11 (23) ◽  
pp. 2906-2922 ◽  
Author(s):  
Yuheng Ma ◽  
Lili Qu ◽  
Zhenming Liu ◽  
Liangren Zhang ◽  
Zhenjun Yang ◽  
...  
Keyword(s):  
Proteasome Inhibitors ◽  
20S Proteasome ◽  
Salinosporamide A

scholarly journals Studies of C-terminal naphthoquinone dipeptides as 20S proteasome inhibitors

2015 ◽  
pp. 1-8 ◽  
Author(s):  
Alessandra Scotti ◽  
Claudio Trapella ◽  
Valeria Ferretti ◽  
Eleonora Gallerani ◽  
Riccardo Gavioli ◽  
...  
Keyword(s):  
Proteasome Inhibitors ◽  
20S Proteasome

Synthesis, Bioactivity, Docking and Molecular Dynamics Studies of Furan-Based Peptides as 20S Proteasome Inhibitors

ChemMedChem ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. 498-510 ◽  
Author(s):  
Qi Sun ◽  
Bo Xu ◽  
Yan Niu ◽  
Fengrong Xu ◽  
Lei Liang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Proteasome Inhibitors ◽  
20S Proteasome

scholarly journals Rational hopping of a peptidic scaffold into non-peptidic scaffolds: structurally novel potent proteasome inhibitors derived from a natural product, belactosin A

2014 ◽  
Vol 50 (19) ◽  
pp. 2445-2447 ◽  
Author(s):  
Shuhei Kawamura ◽  
Yuka Unno ◽  
Takatsugu Hirokawa ◽  
Akira Asai ◽  
Mitsuhiro Arisawa ◽  
...  
Keyword(s):  
Natural Product ◽  
Proteasome Inhibitors ◽  
Pharmacophore Model ◽  
Scaffold Hopping ◽  
Peptide Derivatives

Rational scaffold hopping of a natural product belactosin A derivative based on the pharmacophore model constructed resulted in the identification of the significantly simplified highly potent non-peptide derivatives.

scholarly journals Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Diego Acosta-Alvear ◽  
Min Y Cho ◽  
Thomas Wild ◽  
Tonia J Buchholz ◽  
Alana G Lerner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
New Combination ◽  
20S Proteasome ◽  
Alternative Mechanism ◽  
Combination Therapies ◽  
Response Regulators ◽  
Hallmarks Of Cancer ◽  
Network Rewiring ◽  
Selective Accumulation

Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance.

scholarly journals Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells

2019 ◽  
Author(s):  
Jessica L. Rausch ◽  
Areej A. Ali ◽  
Donna M. Lee ◽  
Yemarshet K. Gebreyohannes ◽  
Keith R. Mehalek ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Proteasome Inhibitors ◽  
Resistance Mutation ◽  
20S Proteasome ◽  
Imatinib Resistance ◽  
Histone H2ax ◽  
Mutational Status ◽  
Ubiquitin Proteasome

ABSTRACTThe majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug’s adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as a therapeutic target.

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