Inhibition of the Human Proteasome by Imidazoline Scaffolds

Azevedo, Lauren M.; Lansdell, Theresa A.; Ludwig, Jacob R.; Mosey, Robert A.; Woloch, Daljinder K.; Cogan, D.P.; Patten, Gregory P.; Kuszpit, Michael R.; Fisk, Jason S.; Tepe, Jetze J.

doi:10.1021/jm400235r

Cited by 37 publications

(24 citation statements)

References 32 publications

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“…These findings represent a new mechanism of proteasome regulation, consistent with our previous findings that these agents effectively block growth in bortezomib resistant THP-1 cells. 59 A similar efficacy was observed among various additional cancer cell lines tested with CC 50 values of 1.6 and 2.4 μ M for multiple myeloma cell line RPMI 8226 and glioblastoma cell line U-87MG, respectively (Figure S8). These studies provide support for the possibility of enhancing 20S selective degradation of intrinsically disordered proteins by modulation of 26S proteasome assembly.…”

Section: Resultssupporting

confidence: 67%

“…Given the antitumor efficacy of this molecule class, we turned our attention to proteins that are overexpressed in certain cancers. 58,59 For these studies, we tested TCH-165 in HEK293T cells expressing ornithine decarboxylase (ODC), labeled with GFPSpark at its N-terminus. 30 GFPSpark is a structured 28 kDa protein and is not degraded by the 20S, whereas the disordered C-terminal of ODC is a well-known 20S substrate (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Our efforts to optimize the activity of the imidazoline scaffold generated the small molecule TCH-165 (Figure 1). 59 Intrigued by conflicting signs of activation and inhibition of proteasome activity in various assays, we pursued a full investigation of its mechanism of action. Here we report that TCH-165 regulates the dynamic equilibrium between the 20S and 26S proteasome complexes, favoring 20S-mediated protein degradation.…”

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confidence: 99%

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Small Molecule Modulation of Proteasome Assembly

et al. 2018

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The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neurodegenerative diseases. Drugs that facilitate 20S-mediated proteolysis therefore have many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small molecule TCH-165, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase, and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome complexes (19S–20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes.

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Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Small Molecule Modulation of Proteasome Assembly

et al. 2018

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“…Examples of nonpeptidic noncovalent proteasome modulators include the phakellins, 25 oxadiazoles, 26 hydroxyureas, 24 imidazolines 27,28 sulfone or piperazine agents, 29 and tamoxifen derivatives. 30 …”

Section: Introductionmentioning

confidence: 99%

Substituted quinolines as noncovalent proteasome inhibitors

McDaniel

Lansdell

Dissanayake

et al. 2016

Bioorganic & Medicinal Chemistry

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Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4 μM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.

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“…17 We evaluated the use of 20S proteasome enhancement for its therapeutic potential in cell culture and in vivo, using the 20S proteasome enhancer, TCH-165. TCH-165 is part of a privileged class of imidazolinebased scaffolds, [18][19][20][21][22][23][24] and is one of the few known molecules shown to enhances 20S mediated proteolysis nearly 10 fold (i.e. 1000%) by favoring a proteolytically active, open-gate 20S proteasome subcomplex.…”

Section: Introductionmentioning

confidence: 99%

Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

Njomen

Lansdell

Vanecek

et al. 2020

Preprint

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Enhancing proteasome activity is a potential new therapeutic strategy to prevent the accumulation of aberrant high levels of protein that drive the pathogenesis of many diseases. Herein, we examine the use of small mole-cules to activate the 20S proteasome to reduce aberrant signaling by the undruggable oncoprotein c-MYC, to treat c-MYC driven oncogenesis. Overexpression of c-MYC is found in more than 50% of all human cancer but remains undruggable because of its highly dynamic intrinsically disordered 3-D conformation, which renders traditional therapeutic strategies largely ineffective. We demonstrate herein that small molecule activation of the 20S proteasome targets dysregulated intrinsically disordered proteins (IDPs), including c-MYC, and reduces can-cer growth in vitro and in vivo models of multiple myeloma, and is even effective in bortezomib resistant cells and unresponsive patient samples. Genomic analysis of various cancer pathways showed that proteasome activation results in downregulation of many c-MYC target genes. Moreover, proteasome enhancement was well tolerated in mice and dogs. These data support the therapeutic potential of 20S proteasome activation in tar-geting IDP-driven proteotoxic disorders, including cancer, and demonstrate that this new therapeutic strategy is well tolerated in vivo.

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Inhibition of the Human Proteasome by Imidazoline Scaffolds

Cited by 37 publications

References 32 publications

Small Molecule Modulation of Proteasome Assembly

Small Molecule Modulation of Proteasome Assembly

Substituted quinolines as noncovalent proteasome inhibitors

Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

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