E1 Enzymes as Therapeutic Targets in Cancer

Barghout, Samir H.; Schimmer, Aaron D.

doi:10.1124/pharmrev.120.000053

Cited by 67 publications

(77 citation statements)

References 510 publications

(883 reference statements)

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“…Recent efforts have focused on the development of compounds that inhibit deubiquitylating (DUB) enzymes 9 as well as the ubiquitin-selective unfoldase p97/valosin containing protein (VCP) 10 . Other experimental compounds target the process of ubiquitylation 11 or ubiquitin itself 12,13 . However, the complex and integrated nature of the UPS makes it hard to predict alternative strategies for obstructing this complex proteolytic pathway in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the ubiquitin-proteasome system by a bioactivatable compound

Haraldsson

et al. 2021

Preprint

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Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-independent, reporter substrates of the UPS, suggesting a selective effect on ubiquitin-dependent proteolysis. In a genome-wide CRISPR interference screen, we identified the redox enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical mediator of CBK77 activity, and further demonstrated its role as the compound bioactivator. Through affinity-based proteomics, we found that CBK77 covalently interacts with ubiquitin. In vitro experiments showed that CBK77-treated ubiquitin conjugates were less susceptible to disassembly by deubiquitylating enzymes. In vivo efficacy of CBK77 was validated by reduced growth of NQO1-proficient human adenocarcinoma cells in nude mice treated with CBK77. This first-in-class NQO1-activatable UPS inhibitor suggests that it may be possible to exploit the intracellular environment in malignant cells for leveraging the impact of compounds that impair the UPS.

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Section: Introductionmentioning

confidence: 99%

Inhibition of the ubiquitin-proteasome system by a bioactivatable compound

Haraldsson

et al. 2021

Preprint

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“…This has been demonstrated by gene ablation studies in yeast and C. elegans where UBA1 is the only ubiquitin E1 (McGrath et al, 1991;Kulkarni and Smith, 2008), but also in various human cancer cell lines (Xu et al, 2010) where UBA6 is apparently not able to compensate for the loss of UBA1. This vital role is further illustrated by the cytotoxic effect of UBA1 inhibitors on mammalian cells (Barghout and Schimmer, 2021).…”

Section: Ubiquitination Enzymes In T Brucei T Cruzi and Leishmaniamentioning

confidence: 99%

“…UBA1 is by far the preferred drug target of the ubiquitinating enzymes because of its position at the apex of the ubiquitination cascade (Barghout and Schimmer, 2021). Moreover, UBA1 has two catalytic domains, of which the ATP-binding adenylation domain is amenable to inhibition by nucleotide mimetics, a well explored strategy of inhibition.…”

Section: Inhibition Of Ubiquitination Uba1 Inhibitorsmentioning

confidence: 99%

“…Two molecules, the natural product largazole and NSC624206 were isolated in cell-based screens for inhibitors of the degradation of the cell cycle inhibitor p27 (Ungermannova et al, 2011;Ungermannova et al, 2012). Largazole inhibits UBA1 at the adenylation step in vitro but its cellular toxicity may primarily be attributed to HDAC inhibition (Ying et al, 2008;Barghout and Schimmer, 2021). NSC624206 inhibits UBA1 at the thioester formation step (Ungermannova et al, 2011).…”

Section: Inhibition Of Ubiquitination Uba1 Inhibitorsmentioning

confidence: 99%

“…MLN4924 is currently tested in phase 1 and 2 clinical trials of various malignancies because of the importance of cullin E3 neddylation in cell cycle progression. TAK-243 and MLN4924 are adenosyl sulfamates that act as AMP mimetics and inhibit E1s in a unique manner that has been termed substrate-assisted inhibition since it requires the activity of the E1 in adenylation and thioester bond formation of ubiquitin (or Nedd8) (Brownell et al, 2010;Barghout and Schimmer, 2021). Thus, the mechanism of TAK-243 involves its binding to the ATP binding site of UBA1, from where its sulfamate NH 2 attacks the UBA1∼ubiquitin thioester bond.…”

Section: Inhibition Of Ubiquitination Uba1 Inhibitorsmentioning

confidence: 99%

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Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

Bijlmakers¹

2021

Front. Chem.

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The eukaryotic pathogens Trypanosoma brucei, Trypanosoma cruzi and Leishmania are responsible for debilitating diseases that affect millions of people worldwide. The numbers of drugs available to treat these diseases, Human African Trypanosomiasis, Chagas' disease and Leishmaniasis are very limited and existing treatments have substantial shortcomings in delivery method, efficacy and safety. The identification and validation of novel drug targets opens up new opportunities for the discovery of therapeutic drugs with better efficacy and safety profiles. Here, the potential of targeting the ubiquitin-proteasome system in these parasites is reviewed. Ubiquitination is the posttranslational attachment of one or more ubiquitin proteins to substrates, an essential eukaryotic mechanism that regulates a wide variety of cellular processes in many different ways. The best studied of these is the delivery of ubiquitinated substrates for degradation to the proteasome, the major cellular protease. However, ubiquitination can also regulate substrates in proteasome-independent ways, and proteasomes can degrade proteins to some extent in ubiquitin-independent ways. Because of these widespread roles, both ubiquitination and proteasomal degradation are essential for the viability of eukaryotes and the proteins that mediate these processes are therefore attractive drug targets in trypanosomatids. Here, the current understanding of these processes in trypanosomatids is reviewed. Furthermore, significant recent progress in the development of trypanosomatid-selective proteasome inhibitors that cure mouse models of trypanosomatid infections is presented. In addition, the targeting of the key enzyme in ubiquitination, the ubiquitin E1 UBA1, is discussed as an alternative strategy. Important differences between human and trypanosomatid UBA1s in susceptibility to inhibitors predicts that the selective targeting of these enzymes in trypanosomatids may also be feasible. Finally, it is proposed that activating enzymes of the ubiquitin-like proteins SUMO and NEDD8 may represent drug targets in these trypanosomatids as well.

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Ablation of Gap Junction Protein Improves the Efficiency of Nanozyme‐Mediated Catalytic/Starvation/Mild‐Temperature Photothermal Therapy

Dong

Akakuru

et al. 2023

Advanced Materials

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Reactive oxygen species (ROS)‐mediated tumor catalytic therapy is typically hindered by gap junction proteins that form cell‐to‐cell channels to remove cytotoxic ROS, thereby protecting tumor cells from oxidative damage. In this work, a multifunctional nanozyme, FePGOGA, is designed and prepared by Fe(III)‐mediated oxidative polymerization (FeP), followed by glucose oxidase (GOx) and GAP19 peptides co‐loading through electrostatic and π–π interactions. The FePGOGA nanozyme exhibits excellent cascade peroxidase‐ and glutathione‐oxidase‐like activities that efficiently catalyze hydrogen peroxide conversion to hydroxyl radicals and convert reduced glutathione to oxidized glutathione disulfide. The loaded GOx starves the tumors and aggravates tumor oxidative stress through glucose decomposition, while GAP19 peptides block the hemichannels by inducing degradation of Cx43, thus increasing the accumulation of intracellular ROS, and decreasing the transport of intracellular glucose. Furthermore, the ROS reacts with primary amines of heat shock proteins to destroy their structure and function, enabling tumor photothermal therapy at the widely sought‐after mild temperature (mildPTT, ≤45 °C). In vivo experiments demonstrate the significant antitumor effectof FePGOGA on cal27 xenograft tumors under near‐infrared light irradiation. This study demonstrates the successful ablation of gap junction proteins to overcome resistance to ROS‐mediated therapy, providing a regulator to suppress tumor self‐preservation during tumor starvation, catalytic therapy, and mildPTT.

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E1 Enzymes as Therapeutic Targets in Cancer

Cited by 67 publications

References 510 publications

Inhibition of the ubiquitin-proteasome system by a bioactivatable compound

Inhibition of the ubiquitin-proteasome system by a bioactivatable compound

Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

Ablation of Gap Junction Protein Improves the Efficiency of Nanozyme‐Mediated Catalytic/Starvation/Mild‐Temperature Photothermal Therapy

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