pevonedistat and Neoplasms

pevonedistat has been researched along with Neoplasms* in 27 studies

Reviews

11 review(s) available for pevonedistat and Neoplasms

ArticleYear
Targeting SUMO Signaling to Wrestle Cancer.
    Trends in cancer, 2021, Volume: 7, Issue:6

    The small ubiquitin-like modifier (SUMO) signaling cascade is critical for gene expression, genome integrity, and cell cycle progression. In this review, we discuss the important role SUMO may play in cancer and how to target SUMO signaling. Recently developed small molecule inhibitors enable therapeutic targeting of the SUMOylation pathway. Blocking SUMOylation not only leads to reduced cancer cell proliferation but also to an increased antitumor immune response by stimulating interferon (IFN) signaling, indicating that SUMOylation inhibitors have a dual mode of action that can be employed in the fight against cancer. The search for tumor types that can be treated with SUMOylation inhibitors is ongoing. Employing SUMO conjugation inhibitory drugs in the years to come has potential as a new therapeutic strategy.

    Topics: Antineoplastic Agents; Cell Cycle; Cell Proliferation; Clinical Trials as Topic; Cyclopentanes; Gene Expression Regulation, Neoplastic; Humans; NEDD8 Protein; Neoplasms; Pyrazoles; Pyrimidines; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Sulfides; Sulfonamides; Sumoylation; Ubiquitin-Activating Enzymes

2021
Targeting Protein Neddylation for Cancer Therapy.
    Advances in experimental medicine and biology, 2020, Volume: 1217

    Neddylation is a posttranslational modification that conjugates a ubiquitin-like protein NEDD8 to substrate proteins. The best-characterized substrates of neddylation are the cullin subunits of cullin-RING E3 ubiquitin ligase complexes (CRLs). CRLs as the largest family of E3 ubiquitin ligases control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins. The process of protein neddylation is overactivated in multiple types of human cancers, providing a sound rationale as an attractive anticancer therapeutic strategy, evidenced by the development of the NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Recently, increasing evidence strongly indicates that neddylation inhibition by MLN4924 exerts anticancer effects mainly by triggering cell apoptosis, senescence, and autophagy and causing angiogenesis suppression, inflammatory responses, and chemo-/radiosensitization in a context-dependent manner. Here, we briefly summarize the latest progresses in this field, focusing on the preclinical studies to validate neddylation modification as a promising anticancer target.

    Topics: Animals; Apoptosis; Autophagy; Cyclopentanes; Humans; NEDD8 Protein; Neoplasms; Pyrimidines; Ubiquitin-Protein Ligases; Ubiquitination

2020
Pharmaceutical Inhibition of Neddylation as Promising Treatments for Various Cancers.
    Current topics in medicinal chemistry, 2019, Volume: 19, Issue:12

    Neddylation is an important post-translational modification of proteins, in which a NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is covalently introduced onto the substrate proteins to regulate their functions and homeostasis. As neddylation is frequently up-regulated in various cancers, its interference was proposed as a promising therapy of related diseases.. The recent advances in developing neddylation interfering agents were summarized to provide an overview of current achievements and perspectives for future development.. Reports on neddylation interfering agents were acquired from Pubmed as well as the EPO and clinicaltrials.gov websites, which were subsequently analyzed and summarized according to targets, chemical structures and biological activities.. Neddylation as a sophisticated procedure comprises proteolytic processing of NEDD8 precursor, deploying conjugating enzymes E1 (NAE), E2 (UBE2M and UBE2F) and various E3, as well as translocating NEDD8 along these conjugating enzymes sequentially and finally to substrate proteins. Among these nodes, NAE, UBE2M and the interaction between UBE2M-DCN1 have been targeted by small molecules, metal complexes, peptides and RNAi. A NAE inhibitor pevonedistat (MLN4924) is currently under evaluation in clinical trials for the treatment of various cancers.. With multiple inhibitory approaches of neddylation being introduced, the development of neddylation interference as a novel cancer therapy is significantly boosted recently, although its efficacy and the best way to achieve that are still to be demonstrated in clinical trials.

    Topics: Antineoplastic Agents; Biological Products; Cyclopentanes; Epigenesis, Genetic; Humans; NEDD8 Protein; Neoplasms; Protein Processing, Post-Translational; Pyrimidines

2019
Neddylation: a novel modulator of the tumor microenvironment.
    Molecular cancer, 2019, 04-03, Volume: 18, Issue:1

    Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition.

    Topics: Cancer-Associated Fibroblasts; Cell Survival; Cellular Senescence; Clinical Trials as Topic; Cyclopentanes; Humans; NEDD8 Protein; Neoplasms; Pyrimidines; Signal Transduction; Tumor Microenvironment

2019
Protein neddylation and its alterations in human cancers for targeted therapy.
    Cellular signalling, 2018, Volume: 44

    Neddylation, a post-translational modification that conjugates an ubiquitin-like protein NEDD8 to substrate proteins, is an important biochemical process that regulates protein function. The best-characterized substrates of neddylation are the cullin subunits of Cullin-RING ligases (CRLs), which, as the largest family of E3 ubiquitin ligases, control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins. Recently, increasing pieces of experimental evidence strongly indicate that the process of protein neddylation modification is elevated in multiple human cancers, providing sound rationale for its targeting as an attractive anticancer therapeutic strategy. Indeed, neddylation inactivation by MLN4924 (also known as pevonedistat), a small molecule inhibitor of E1 NEDD8-activating enzyme currently in phase I/II clinical trials, exerts significant anticancer effects by inducing cell cycle arrest, apoptosis, senescence and autophagy in a cell-type and context dependent manner. Here, we summarize the latest progresses in the field with a major focus on preclinical studies in validation of neddylation modification as a promising anticancer target.

    Topics: Apoptosis; Autophagy; Cell Cycle Checkpoints; Cellular Senescence; Cyclopentanes; Humans; Molecular Targeted Therapy; Neoplasms; Protein Processing, Post-Translational; Pyrimidines; Ubiquitin-Activating Enzymes; Ubiquitin-Protein Ligases

2018
MLN4924 therapy as a novel approach in cancer treatment modalities.
    Journal of chemotherapy (Florence, Italy), 2016, Volume: 28, Issue:2

    MLN4924 is an investigational and a newly discovered small molecule that is a potent and selective inhibitor of the NEDD8 (Neural precursor cell-Expressed Developmentally down-regulated 8) Activating Enzyme (NAE), a pivotal regulator of the Cullin Ring Ligases E3 (CRL), which has been implicated recently in DNA damage. MLN4924 effectively inhibits tumour cell growth by inducing all three common types of death, namely apoptosis, autophagy and senescence and it was also reported that the formation of capillary vessels was significantly suppressed by MLN4924.In this review, we are going to highlight the molecular mechanism of MLN4924 in cancer therapy and its pros and cons in cancer therapy.

    Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Cycle Proteins; Cullin Proteins; Cyclopentanes; Humans; Neoplasms; NF-KappaB Inhibitor alpha; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Radiation-Sensitizing Agents

2016
Neddylation Pathway as a Novel Anti-cancer Target: Mechanistic Investigation and Therapeutic Implication.
    Anti-cancer agents in medicinal chemistry, 2015, Volume: 15, Issue:9

    Protein neddylation, a newly characterized posttranslational modification that adds the ubiquitin-like molecule NEDD8 to substrates, modulates important biological processes, whereas dysfunction of neddylation may cause several serious diseases, such as cancer. Inhibition of neddylation pathway has emerged as a promising anticancer strategy, as evidenced by development of the NEDD8-activating enzyme (NAE) inhibitor MLN4924. Due to its potent anti-cancer efficacy and well-tolerated toxicity, MLN4924 has been evaluated in multiple Phase I clinical trials for solid tumors and hematologic malignancies. Recently, accumulating evidences indicate that neddylation pathway also plays a pivotal role in the regulation of multiple processes of tumor microenvironment (TME), such as tumor angiogenesis and the function of immune cells. In this review, we briefly summarize the latest progresses in this field and highlight neddylation pathway as an attractive therapeutic target against human cancer.

    Topics: Antineoplastic Agents; Cyclopentanes; Humans; Macrophages; NEDD8 Protein; Neoplasms; Neovascularization, Pathologic; Pyrimidines; Ubiquitins

2015
Negative regulation of NEDD8 conjugation pathway by novel molecules and agents for anticancer therapy.
    Current pharmaceutical design, 2013, Volume: 19, Issue:22

    Tumor cells frequently promote the dysregulation of the cell cycle and escape from apoptotic cell death triggered by a number of cellular stresses. Programmed proteolytic degradation of regulatory proteins via the ubiquitin-proteasome pathway is crucial for homeostasis of numerous biological processes. Disruption of this system is one of the factors that promote aberrant cell-proliferation. The small ubiquitin-like protein, NEDD8, has been identified as a fundamental regulator of the activity of the E3 ubiquitin ligases called the SCF complex (consisting of Skp-1, cullin, and F-box protein) or CRL (cullin-RING ubiquitin ligase) which control a final step in ubiquitination of diverse substrates associated with cancer biology. The ubiquitin ligase activity of the SCF complex requires NEDD8 to covalently bind to cullins. To a large extent, exploring the negative regulation system of the NEDD8 pathway is expected to lead to the development of novel anticancer targets. This review focuses on the NEDD8 negative regulation system including chemical compounds such as MLN4924 and protein molecules (e.g. COP9 signalosome, CAND1, inactive mutant of Ubc12 and NUB1/NUB1L) and clarifies possible strategies for targeting the NEDD8 cascade in cancer cells.

    Topics: Antineoplastic Agents; Cyclopentanes; Humans; NEDD8 Protein; Neoplasms; Proteasome Endopeptidase Complex; Pyrimidines; Ubiquitins

2013
Novel roles of Skp2 E3 ligase in cellular senescence, cancer progression, and metastasis.
    Chinese journal of cancer, 2012, Volume: 31, Issue:4

    S-phase kinase-associated protein 2 (Skp2) belongs to the F-box protein family. It is a component of the SCF E3 ubiquitin ligase complex. Skp2 has been shown to regulate cellular proliferation by targeting several cell cycle-regulated proteins for ubiquitination and degradation, including cyclin-dependent kinase inhibitor p27. Skp2 has also been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers. This review discusses the recent discoveries on the novel roles of Skp2 in regulating cellular senescence, cancer progression, and metastasis, as well as the therapeutic potential of targeting Skp2 for human cancer treatment.

    Topics: Animals; Cell Movement; Cellular Senescence; Cyclopentanes; Disease Progression; Drug Delivery Systems; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Pyrimidines; S-Phase Kinase-Associated Proteins; Ubiquitination

2012
Inhibition of NEDD8-conjugation pathway by novel molecules: potential approaches to anticancer therapy.
    Molecular oncology, 2012, Volume: 6, Issue:3

    Cancer cells can survive through the upregulation of cell cycle and the escape from apoptosis induced by numerous cellular stresses. In the normal cells, these biological cascades depend on scheduled proteolytic degradation of regulatory proteins via the ubiquitin-proteasome pathway. Therefore, interruption of regulated proteolytic pathways leads to abnormal cell-proliferation. Ubiquitin ligases called SCF complex (consisting of Skp-1, cullin, and F-box protein) or CRL (cullin-RING ubiquitin ligase) are predominant in a family of E3 ubiquitin ligases that control a final step in ubiquitination of diverse substrates. To a great extent, the ubiquitin ligase activity of the SCF complex requires the conjugation of NEDD8 to cullins, i.e. scaffold proteins. This review is anticipated to review the downregulation system of NEDD8 conjugation by several factors including a chemical compound such as MLN4924 and protein molecules (e.g. COP9 signalosome, inactive mutant of Ubc12, and NUB1/NUB1L). Since the downregulation of NEDD8 conjugation affects cell-cycle progression by inhibiting the ligase activity of SCF complexes, such knowledge in the NEDD8-conjugation pathway will contribute to the more magnificent therapies that selectively suppress tumorigenesis.

    Topics: Animals; Cyclopentanes; Humans; NEDD8 Protein; Neoplasms; Pyrimidines; Signal Transduction; SKP Cullin F-Box Protein Ligases; Ubiquitins

2012
MLN4924: a novel first-in-class inhibitor of NEDD8-activating enzyme for cancer therapy.
    Expert opinion on investigational drugs, 2012, Volume: 21, Issue:10

    The small ubiquitin-like molecule NEDD8 has been identified as an essential regulator of the activity of the cullin-RING E3 ubiquitin ligases (CRLs), which control the turnover of multiple proteins with fundamental roles in cancer biology. The aberrant function of the NEDD8 cascade within the context of malignancy makes it an attractive target for the development of novel anticancer agents. MLN4924 is a first-in-class inhibitor of the proximal regulator of the NEDD8 system (NEDD8-activating enzyme, NAE) that has entered Phase-I trials for cancer therapy and has established that significant therapeutic benefit can be achieved by antagonizing NEDD8-mediated protein degradation.. This review provides a detailed overview of the NEDD8 system and discusses the mechanisms of action of MLN4924, a novel small molecule NAE inhibitor. Key findings from preclinical investigations of MLN4924 in a broad range of cancer models and preliminary findings from ongoing Phase-I clinical trials with MLN4924 are also discussed.. Targeting protein NEDDylation represents an exciting new anticancer strategy with demonstrable therapeutic benefit. Ongoing and future studies focused on dissecting the functional status/regulation of the NEDD8 system in individual tumor types will facilitate the design of novel approaches that yield optimal therapeutic benefit.

    Topics: Animals; Antineoplastic Agents; Cyclopentanes; Humans; NEDD8 Protein; Neoplasms; Pyrimidines; Ubiquitins

2012

Trials

2 trial(s) available for pevonedistat and Neoplasms

ArticleYear
Effect of CYP3A inhibitors on the pharmacokinetics of pevonedistat in patients with advanced solid tumours.
    British journal of clinical pharmacology, 2019, Volume: 85, Issue:7

    This phase I study evaluated the effects of the moderate cytochrome P450 (CYP) 3A inhibitor fluconazole and the strong CYP3A/P-glycoprotein (P-gp) inhibitor itraconazole on the pharmacokinetics of the investigational neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme inhibitor pevonedistat in patients with advanced solid tumours.. The ratios of geometric mean area under the concentration-time curves (n; 90% confidence interval) of pevonedistat in the presence vs. absence of fluconazole or itraconazole were 1.11 (12; 1.03-1.19) and 1.14 (33; 1.07-1.23), respectively. Fifty patients (98%) experienced at least one adverse event (AE), with maximum severity of grade 1-2 in 28 patients (55%) and of grade ≥3 in 22 patients (43%). The most common drug-related AEs were vomiting (12%), diarrhoea (10%) and nausea (8%). No new safety findings were observed for pevonedistat.. Fluconazole or itraconazole had insignificant effects on pevonedistat pharmacokinetics, indicating minor contributions of CYP3A/P-gp to pevonedistat clearance. The safety profile of single doses of pevonedistat plus steady-state fluconazole or itraconazole was consistent with prior clinical experience, with no new safety signals observed.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Cyclopentanes; Cytochrome P-450 CYP3A Inhibitors; Docetaxel; Drug Interactions; Enzyme Inhibitors; Female; Fluconazole; Humans; Itraconazole; Male; Middle Aged; Neoplasms; Paclitaxel; Pyrimidines

2019
Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2016, Feb-15, Volume: 22, Issue:4

    To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies.. Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0.. Schedule A MTD was 50 mg/m(2); based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m(2), respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥ 3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies.. Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cyclopentanes; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pyrimidines; Treatment Outcome; Tumor Burden; Ubiquitin-Activating Enzymes

2016

Other Studies

14 other study(ies) available for pevonedistat and Neoplasms

ArticleYear
Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication.
    Molecular cancer therapeutics, 2023, 08-01, Volume: 22, Issue:8

    Schlafen 11 (SLFN11) is an increasingly prominent predictive biomarker and a molecular sensor for a wide range of clinical drugs: topoisomerases, PARP and replication inhibitors, and platinum derivatives. To expand the spectrum of drugs and pathways targeting SLFN11, we ran a high-throughput screen with 1,978 mechanistically annotated, oncology-focused compounds in two isogenic pairs of SLFN11-proficient and -deficient cells (CCRF-CEM and K562). We identified 29 hit compounds that selectively kill SLFN11-proficient cells, including not only previously known DNA-targeting agents, but also the neddylation inhibitor pevonedistat (MLN-4924) and the DNA polymerase α inhibitor AHPN/CD437, which both induced SLFN11 chromatin recruitment. By inactivating cullin-ring E3 ligases, pevonedistat acts as an anticancer agent partly by inducing unscheduled re-replication through supraphysiologic accumulation of CDT1, an essential factor for replication initiation. Unlike the known DNA-targeting agents and AHPN/CD437 that recruit SLFN11 onto chromatin in 4 hours, pevonedistat recruited SLFN11 at late time points (24 hours). While pevonedistat induced unscheduled re-replication in SLFN11-deficient cells after 24 hours, the re-replication was largely blocked in SLFN11-proficient cells. The positive correlation between sensitivity to pevonedistat and SLFN11 expression was also observed in non-isogenic cancer cells in three independent cancer cell databases (NCI-60, CTRP: Cancer Therapeutics Response Portal and GDSC: Genomic of Drug Sensitivity in Cancer). The present study reveals that SLFN11 not only detects stressed replication but also inhibits unscheduled re-replication induced by pevonedistat, thereby enhancing its anticancer efficacy. It also suggests SLFN11 as a potential predictive biomarker for pevonedistat in ongoing and future clinical trials.

    Topics: Antineoplastic Agents; Cell Line, Tumor; Chromatin; Cyclopentanes; Humans; Neoplasms; Nuclear Proteins

2023
Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, sensitizes cancer cells to VSVΔ51 oncolytic virotherapy.
    Molecular therapy : the journal of the American Society of Gene Therapy, 2023, 11-01, Volume: 31, Issue:11

    The clinical efficacy of VSVΔ51 oncolytic virotherapy has been limited by tumor resistance to viral infection, so strategies to transiently repress antiviral defenses are warranted. Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor currently being tested in clinical trials for its antitumor potential. In this study, we demonstrate that pevonedistat sensitizes human and murine cancer cells to increase oncolytic VSVΔ51 infection, increase tumor cell death, and improve therapeutic outcomes in resistant syngeneic murine cancer models. Increased VSVΔ51 infectivity was also observed in clinical human tumor samples. We further identify the mechanism of this effect to operate via blockade of the type 1 interferon (IFN-1) response through neddylation-dependent interferon-stimulated growth factor 3 (ISGF3) repression and neddylation-independent inhibition of NF-κB nuclear translocation. Together, our results identify a role for neddylation in regulating the innate immune response and demonstrate that pevonedistat can improve the therapeutic outcomes of strategies using oncolytic virotherapy.

    Topics: Animals; Cell Line, Tumor; Enzyme Inhibitors; Humans; Interferons; Mice; NEDD8 Protein; Neoplasms; Oncolytic Virotherapy

2023
Oncolytic virus and inhibitor for NEDD8-activating enzyme pevonedistat: Promising combination for cancer therapy?
    Molecular therapy : the journal of the American Society of Gene Therapy, 2023, 11-01, Volume: 31, Issue:11

    Topics: Antineoplastic Agents; Cyclopentanes; Enzyme Inhibitors; Humans; NEDD8 Protein; Neoplasms; Oncolytic Viruses

2023
PD-L1 induction via the MEK-JNK-AP1 axis by a neddylation inhibitor promotes cancer-associated immunosuppression.
    Cell death & disease, 2022, 10-03, Volume: 13, Issue:10

    MLN4924 is a first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE), which is currently in several clinical trials for anti-cancer applications. However, MLN4924 also showed some off-target effects with potential to promote the growth of cancer cells which counteracts its anticancer activity. In this study, we found that MLN4924 increases the levels of PD-L1 mRNA and protein in dose- and time-dependent manners. Mechanistic study showed that this MLN4924 effect is largely independent of neddylation inactivation, but is due to activation of both ERK and JNK signals, leading to AP-1 activation, which is blocked by the small molecule inhibitors of MEK and JNK, respectively. Biologically, MLN4924 attenuates T cell killing in a co-culture model due to PD-L1 upregulation, which can be, at least in part, abrogated by either MEK inhibitor or anti-PD-L1 antibody. In an in vivo BALB/c mouse xenograft tumor model, while MLN4924 alone had no effect, combination with either MEK inhibitor or anti-PD-L1 antibody enhanced the suppression of tumor growth. Taken together, our study provides a sound rationale for effective anticancer therapy in combination of anti-PD-L1 antibody or MEK inhibitor with MLN4924 to overcome the side-effect of immunosuppression by MLN4924 via PD-L1 induction.

    Topics: Animals; Apoptosis; Cell Line, Tumor; Cyclopentanes; Humans; Immunosuppression Therapy; Mice; Mitogen-Activated Protein Kinase Kinases; NEDD8 Protein; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; RNA, Messenger; Transcription Factor AP-1

2022
Targeting oncogenic SOX2 in human cancer cells: therapeutic application.
    Protein & cell, 2020, Volume: 11, Issue:2

    Topics: Antineoplastic Agents; Cyclopentanes; Humans; Neoplasms; Neoplastic Stem Cells; Pyrimidines; SOXB1 Transcription Factors

2020
Overexpression of ABCG2 confers resistance to pevonedistat, an NAE inhibitor.
    Experimental cell research, 2020, 03-15, Volume: 388, Issue:2

    Pevonedistat is a potent, selective, first-in-class NEDD8 activating enzyme inhibitor. It is now under multiple clinical trials that investigate its anticancer effect against solid tumors and leukemia. ATP-binding cassette (ABC) transporters are membrane proteins that are involved in mediating multidrug resistance (MDR). In this article, we reveal that pevonedistat is a substrate of ABCG2 which decreases the therapeutic effect of pevonedistat. The cytotoxicity of pevonedistat was significantly weakened in ABCG2-overexpressing cells, and the drug resistance can be reversed by ABCG2 inhibitors. The ATPase assay suggested that pevonedistat can stimulate ABCG2 ATPase activity in a concentration-dependent manner. Pevonedistat showed little effect on the expression level or subcellular localization of ABCG2 after 72 h treatment. Furthermore, a pevonedistat resistance cell line S1-PR was established and overexpressed ABCG2. Generally, our study provides evidence that ABCG2 can be a prominent factor leading to pevonedistat-resistance. Furthermore, ABCG2 may also be utilized as a biomarker to monitor the development of pevonedistat resistance during cancer treatment.

    Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Cyclopentanes; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Neoplasm Proteins; Neoplasms; Pyrimidines; Tumor Cells, Cultured; Ubiquitin-Activating Enzymes

2020
Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate-mediated regulation of cullin-RING ligase and sensitize cancer cells to MLN4924/pevonedistat.
    The Journal of biological chemistry, 2020, 07-24, Volume: 295, Issue:30

    Topics: Benzenesulfonates; Cullin Proteins; Cyclopentanes; Enzyme Inhibitors; HCT116 Cells; HEK293 Cells; Humans; Neoplasm Proteins; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Phytic Acid; Pyrimidines; Suramin

2020
Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells.
    JCI insight, 2019, 02-21, Volume: 4, Issue:4

    Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types of cancer cells. Whether and how neddylation modification affects cellular metabolism remains largely unknown. Here, we showed that MLN4924, a small-molecule inhibitor of neddylation modification, induces mitochondrial fission-to-fusion conversion in breast cancer cells via inhibiting ubiquitylation and degradation of fusion-promoting protein mitofusin 1 (MFN1) by SCFβ-TrCP E3 ligase and blocking the mitochondrial translocation of fusion-inhibiting protein DRP1. Importantly, MLN4924-induced mitochondrial fusion is independent of cell cycle progression, but confers cellular survival. Mass-spectrometry-based metabolic profiling and mitochondrial functional assays reveal that MLN4924 inhibits the TCA cycle but promotes mitochondrial OXPHOS. MLN4924 also increases glycolysis by activating PKM2 via promoting its tetramerization. Biologically, MLN4924 coupled with the OXPHOS inhibitor metformin, or the glycolysis inhibitor shikonin, significantly inhibits cancer cell growth both in vitro and in vivo. Together, our study links neddylation modification and energy metabolism, and provides sound strategies for effective combined cancer therapies.

    Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclopentanes; Energy Metabolism; Female; GTP Phosphohydrolases; HEK293 Cells; Humans; Metformin; Mice; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins; Naphthoquinones; Neoplasms; Oxidative Phosphorylation; Proteolysis; Pyrimidines; Ubiquitin-Activating Enzymes; Ubiquitination; Xenograft Model Antitumor Assays

2019
The E3 ligase C-CBL inhibits cancer cell migration by neddylating the proto-oncogene c-Src.
    Oncogene, 2018, Volume: 37, Issue:41

    Neddylation is a cellular process that covalently conjugates substrate proteins with the small ubiquitin-like molecule NEDD8. As neddylation is required for fast turnover of proteins in proliferating cancer cells, the neddylation process is currently regarded as a potential target for cancer therapy. However, little is known about the role of neddylation in cancer invasion and metastasis. Unexpectedly, we here found that the neddylation blockade stimulates migration of lung cancer and glioblastoma cells. Mechanistically, C-CBL acts as the E3 ligase for neddylation of the proto-oncogene c-Src. After neddylation, c-Src is poly-ubiquitinated and degraded through the proteasome, which inhibits the PI3K-AKT pathway responsible for cell migration. In human lung cancer tissues, the downregulation of C-CBL was associated with c-Src/AKT, cancer metastasis, and poor survival in patients. Therefore, C-CBL is likely to play a tumor suppressive role by antagonizing a robust oncogenic signaling driven by c-Src. This study provides new insight about the role of neddylation in cancer metastasis. It also implies that the metastasis risk should be carefully evaluated before the clinical application of neddylation inhibitors as anticancer regimens.

    Topics: Cell Line, Tumor; Cell Movement; Cyclopentanes; Enzyme Inhibitors; Genes, src; Genes, Tumor Suppressor; Glioblastoma; Humans; Lung Neoplasms; NEDD8 Protein; Neoplasms; Proto-Oncogene Mas; Proto-Oncogene Proteins c-cbl; Pyrimidines

2018
Applications of pathology-assisted image analysis of immunohistochemistry-based biomarkers in oncology.
    Veterinary pathology, 2014, Volume: 51, Issue:1

    Immunohistochemistry-based biomarkers are commonly used to understand target inhibition in key cancer pathways in preclinical models and clinical studies. Automated slide-scanning and advanced high-throughput image analysis software technologies have evolved into a routine methodology for quantitative analysis of immunohistochemistry-based biomarkers. Alongside the traditional pathology H-score based on physical slides, the pathology world is welcoming digital pathology and advanced quantitative image analysis, which have enabled tissue- and cellular-level analysis. An automated workflow was implemented that includes automated staining, slide-scanning, and image analysis methodologies to explore biomarkers involved in 2 cancer targets: Aurora A and NEDD8-activating enzyme (NAE). The 2 workflows highlight the evolution of our immunohistochemistry laboratory and the different needs and requirements of each biological assay. Skin biopsies obtained from MLN8237 (Aurora A inhibitor) phase 1 clinical trials were evaluated for mitotic and apoptotic index, while mitotic index and defects in chromosome alignment and spindles were assessed in tumor biopsies to demonstrate Aurora A inhibition. Additionally, in both preclinical xenograft models and an acute myeloid leukemia phase 1 trial of the NAE inhibitor MLN4924, development of a novel image algorithm enabled measurement of downstream pathway modulation upon NAE inhibition. In the highlighted studies, developing a biomarker strategy based on automated image analysis solutions enabled project teams to confirm target and pathway inhibition and understand downstream outcomes of target inhibition with increased throughput and quantitative accuracy. These case studies demonstrate a strategy that combines a pathologist's expertise with automated image analysis to support oncology drug discovery and development programs.

    Topics: Algorithms; Animals; Apoptosis; Aurora Kinase A; Automation; Azepines; Biomarkers, Pharmacological; Biopsy; Cyclopentanes; Drug Discovery; Drug Evaluation, Preclinical; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Mitosis; Neoplasms; Pyrimidines; Skin

2014
Inactivation of the Cullin (CUL)-RING E3 ligase by the NEDD8-activating enzyme inhibitor MLN4924 triggers protective autophagy in cancer cells.
    Autophagy, 2012, Volume: 8, Issue:11

    The multiunit Cullin (CUL)-RING E3 ligase (CRL) controls diverse biological processes by targeting a mass of substrates for ubiquitination and degradation, whereas its dysfunction causes carcinogenesis. Post-translational neddylation of CUL, a process triggered by the NEDD8-activating enzyme E1 subunit 1 (NAE1), is required for CRL activation. Recently, MLN4924 was discovered via a high-throughput screen as a specific NAE1 inhibitor and first-in-class anticancer drug. By blocking CUL neddylation, MLN4924 inactivates CRL and causes the accumulation of CRL substrates that trigger cell cycle arrest, senescence and/or apoptosis to suppress the growth of cancer cells in vitro and in vivo. Recently, we found that MLN4924 also triggers protective autophagy in response to CRL inactivation. MLN4924-induced autophagy is attributed partially to the inhibition of mechanistic target of rapamycin (also known as mammalian target of rapamycin, MTOR) activity by the accumulation of the MTOR inhibitory protein DEPTOR, as well as reactive oxygen species (ROS)-induced stress. Moreover, the blockage of autophagy response enhances apoptosis in MLN4924-treated cells. Together, our findings not only reveal autophagy as a novel cellular response to CRL inactivation by MLN4924, but also provide a piece of proof-of-concept evidence for the combination of MLN4924 with autophagy inhibitors to enhance therapeutic efficacy.

    Topics: Animals; Autophagy; Cullin Proteins; Cyclopentanes; Cytoprotection; Enzyme Activation; Enzyme Inhibitors; Gene Knockdown Techniques; Humans; Mice; Models, Biological; Neoplasms; Pyrimidines; Reactive Oxygen Species; Ubiquitin-Protein Ligases; Ubiquitins

2012
SUMO, Ubiquitin, UBL Proteins: Implications For Human Diseases - Fifth International Conference.
    IDrugs : the investigational drugs journal, 2010, Volume: 13, Issue:4

    The fifth international conference on SUMO, Ubiquitin, UBL Proteins: Implications for Human Diseases, held in Houston, included topics covering the latest advances and new targets in the field of protein modification. This conference report highlights selected presentations on the structural characterization of ubiquitination and SUMOylation machinery; the regulation of ubiquitination enzymes, including E3 ligases; the functions and mechanism of action of SUMO-targeted ubiquitin ligases (STUbLs); the regulation of gene expression by SUMO; non-degradative functions of ubiquitin and SUMO in signal transduction; mechanisms and functions of ISG15 conjugation; the interaction of pathogens with host cell SUMOylation machinery; and stabilization of the Axin protein. Investigational drugs discussed include MLN-4924 (Millennium Pharmaceuticals Inc).

    Topics: Allosteric Regulation; Bacterial Toxins; Communicable Diseases; Cyclopentanes; Cytokines; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation; Heat-Shock Proteins; Hemolysin Proteins; Heterocyclic Compounds, 3-Ring; Humans; NEDD8 Protein; Neoplasms; Nuclear Proteins; Protein Processing, Post-Translational; Pyrimidines; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Tankyrases; Transcription Factors; Ubiquitin; Ubiquitin-Activating Enzymes; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligases; Ubiquitination; Ubiquitins

2010
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.
    Nature, 2009, Apr-09, Volume: 458, Issue:7239

    The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cells, Cultured; Cullin Proteins; Cyclopentanes; Enzyme Inhibitors; Female; Humans; Mice; NEDD8 Protein; Neoplasms; Proteasome Inhibitors; Pyrimidines; Transplantation, Heterologous; Ubiquitin-Activating Enzymes; Ubiquitins

2009
Targeting NEDD8-activated cullin-RING ligases for the treatment of cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2009, Jun-15, Volume: 15, Issue:12

    E3 ubiquitin ligases regulate many dynamic cellular processes important for cancer cell survival. Together with ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzymes (E2s), E3s catalyze the ubiquitination of numerous protein substrates that are subsequently targeted to the 26S proteasome for degradation. The clinical success of the proteasome inhibitor bortezomib has encouraged the evaluation of other components of the ubiquitin proteasome system for pharmaceutical intervention. Targeting specific E3s is particularly attractive because there is the potential to selectively block the degradation of certain cellular proteins and possibly avoid unwanted effects on other proteins. The cullin-RING ubiquitin E3 ligases (CRLs) represent the largest subfamily of E3s. The requirement that CRLs be activated by NEDD8 modification on the cullin protein offers an "achilles heel" for modulating this entire subfamily. NEDD8-activating enzyme (NAE) catalyzes the first step in the NEDD8 pathway and as such controls the activity of CRLs. In this article, we describe the role of the NEDD8 pathway in activating CRLs and discuss the preclinical findings with a first-in-class NAE inhibitor that is currently in phase I clinical trials for both solid tumor and hematological malignancies. In addition, we speculate where NAE inhibitors may find clinical utility.

    Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Cullin Proteins; Cyclopentanes; Humans; NEDD8 Protein; Neoplasms; NF-kappa B; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Pyrimidines; RING Finger Domains; Signal Transduction; Ubiquitin-Activating Enzymes; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligases; Ubiquitins

2009
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