Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

Landré, Vivien; Rotblat, Barak; Melino, Sonia; Bernassola, Francesca; Melino, Gerry

doi:10.18632/oncotarget.2431

Cited by 86 publications

(74 citation statements)

References 277 publications

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“…These include PYR-41 and PYZD-4409, the first cell-permeable compounds that are currently in preclinical development stage. Their therapeutic potential originates from their ability to inhibit the catalytic activity of UBE1, the main ubiquitin-activating enzyme in humans (330). However, similar to proteasome inhibitors, these drugs affect many substrates, which could limit their therapeutic value.…”

Section: Implications For Drug Designmentioning

confidence: 99%

“…The other two members of the p53 family, p63 and p73, are targeted for degradation by the E3 ligase ITCH (330). Because p63 and p73 share some of the functions of p53, blocking their degradation may be a promising therapeutic strategy, and cyclic peptides that interfere with the binding of ITCH to these targets have been identified (342).…”

Section: Implications For Drug Designmentioning

confidence: 99%

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Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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Section: Implications For Drug Designmentioning

confidence: 99%

Section: Implications For Drug Designmentioning

confidence: 99%

Degrons in cancer

et al. 2017

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“…The genes involved in specific pathways regarding the proteasome inhibitors, and particularly bortezomib, are related to the critical pathological events of MM such as tumor angiogenesis and neoplastic signaling pathways (cadherin, integrin, Wnt, GnRH, ubiquitin), as well as chemokine-mediated inflammation (Table 1). Those pathways are essentially important in the biology of myeloma, such as the ubiquitin proteasome system, which plays a role in the regulation of most cellular pathways, and its deregulation in MM represents a target for proteasome inhibition via bortezomib [20]. Proliferation and apoptosis pathways are pathologically regulated by the ubiquitin-proteasome system, resulting in cellular neoplastic transformation in MM [21].…”

Section: Discussionmentioning

confidence: 99%

Expression Profiles of the Individual Genes Corresponding to the Genes Generated by Cytotoxicity Experiments with Bortezomib in Multiple Myeloma

Ghasemi¹,

Alpsoy²,

Turk³

et al. 2016

Tjh

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Objective:Multiple myeloma (MM) is currently incurable due to refractory disease relapse even under novel anti-myeloma treatment. In silico studies are effective for key decision making during clinicopathological battles against the chronic course of MM. The aim of this present in silico study was to identify individual genes whose expression profiles match that of the one generated by cytotoxicity experiments for bortezomib.Materials and Methods:We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of metadata derived from relevant information. The E-MTAB-783 dataset containing expression data from 789 cancer cell lines including 8 myeloma cell lines with drug screening data from the Wellcome Trust Sanger Institute database obtained from ArrayExpress was “Robust Multi-array analysis” normalized using GeneSpring v.12.5. Drug toxicity data were obtained from the Genomics of Drug Sensitivity in Cancer project. In order to identify individual genes whose expression profiles matched that of the one generated by cytotoxicity experiments for bortezomib, we used a linear regression-based approach, where we searched for statistically significant correlations between gene expression values and IC50 data. The intersections of the genes were identified in 8 cell lines and used for further analysis.Results:Our linear regression model identified 73 genes and some genes expression levels were found to very closely correlated with bortezomib IC50 values. When all 73 genes were used in a hierarchical cluster analysis, two major clusters of cells representing relatively sensitive and resistant cells could be identified. Pathway and molecular function analysis of all the significant genes was also investigated, as well as the genes involved in pathways.Conclusion:The findings of our present in silico study could be important not only for the understanding of the genomics of MM but also for the better arrangement of the targeted anti-myeloma therapies, such as bortezomib.

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“…Although the knowledge base for ubiquitination is far less well developed than that for phosphorylation, more than 311 of the 448 proteins in our DDR set have been reported to be subject to ubiquitination of one sort or another, while 36 are also reported subject to modification by the ubiquitin-related SUMO protein (Supplementary information S15 (table)). This widespread involvement of ubiquitin (and SUMO) modifications in DDR regulation, suggests that this system may offer opportunities for therapeutic intervention in cancer 62 .…”

Section: Ddr Regulation By Ubiquitin Like Phosphorylation Ubiquitinmentioning

confidence: 99%

Therapeutic opportunities within the DNA damage response

et al. 2015

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The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell and its disruption is one of the 'Hallmarks of Cancer'. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer by radiation therapies or by genotoxic chemotherapies. More recently, protein components of the DDR systems are being identified as promising avenues for targeted cancer therapeutics. Here we present an in-depth analysis of the function, disease role and therapeutic potential of ~450 expert-curated human DDR genes. We discuss the current state of DDR drugs both FDA approved or under clinical investigation. We examine large-scale genomic and expression data in 15 cancers to identify deregulated components of the DDR in these tumours, and we apply systematic computational analysis to identify DDR proteins amenable to modulation by small molecules, highlighting potential novel therapeutic targets. 3The DNA Damage Response (DDR) evolved in response to the exposure of the genome to exogenous and endogenous genotoxins. Unless repaired in an error-free process, DNA damage can result in mutations and altered cellular behavior. Consequently, cells deploy a diverse repertoire of mechanisms to maintain genetic integrity 1 (see TABLE 1). These mechanisms involve the DNA repair processes themselves, the systems that regulate and organize them, and the systems that integrate DNA damage repair with the cell cycle 2 .Disruption of the DDR is observed in many cancers [3][4][5] , and underlies the genomic instability that accompanies tumourigenesis and progression. However, in the majority of cases, the specific underlying defects are poorly characterised 6,7 . Conversely, there are well-described cancers where disruption of a DDR mechanism is directly causal. In addition to these licensed drugs, there are a number of compounds currently under clinical evaluation that target DDR pathways directly. These targets include the protein kinases involved in cell cycle DNA checkpoint for DNA damage and/or replicative stress (eg CHEK1, WEE1), and individual enzymes involved in base excision repair (BER; APEX1), direct repair (MGMT), non-homologous DNA double strand break repair (NHEJ; PRKDC / DNA-PK) and telomere maintenance (TM; TERT).The initial rationale for development of DDR enzyme-targeted drugs focused on their use as potentiators, inhibiting repair of damage caused by radiotherapy and/or conventional genotoxins 11 .However, this approach has been extended to stand-alone use, targeting DNA repair pathways critical to tumour survival by exploiting synthetic sensitivity/lethality 16 (SSL). SSL arises when a combination of loss-of-function in two or more genes leads to cell death, while loss-of-function in only one of them does not. The therapeutic aim is to exploit genetic defects essential to a tumour's survival by combining the defect in an affected pathway with a pharmacologically induced defect in a compensating pathway 17 . 4The best example to date is the pharmaceutical inhibition...

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Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

Cited by 86 publications

References 277 publications

Degrons in cancer

Degrons in cancer

Expression Profiles of the Individual Genes Corresponding to the Genes Generated by Cytotoxicity Experiments with Bortezomib in Multiple Myeloma

Therapeutic opportunities within the DNA damage response

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