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MLN4924

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https://www.readbyqxmd.com/read/27901050/the-use-of-the-nedd8-inhibitor-mln4924-pevonedistat-in-a-cyclotherapy-approach-to-protect-wild-type-p53-cells-from-mln4924-induced-toxicity
#1
Lara J Bou Malhab, Simon Descamps, Benedicte Delaval, Dimitris P Xirodimas
Targetting the ubiquitin pathway is an attractive strategy for cancer therapy. The inhibitor of the ubiquitin-like molecule NEDD8 pathway, MLN4924 (Pevonedistat) is in Phase II clinical trials. Protection of healthy cells from the induced toxicity of the treatment while preserving anticancer efficacy is a highly anticipated outcome in chemotherapy. Cyclotherapy was proposed as a promising approach to achieve this goal. We found that cytostatic activation of p53 protects cells against MLN4924-induced toxicity and importantly the effects are reversible...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27821554/assessment-of-drug-sensitivity-in-hematopoietic-stem-and-progenitor-cells-from-acute-myelogenous-leukemia-and-myelodysplastic-syndrome-ex-vivo
#2
Katherine L B Knorr, Laura E Finn, B Douglas Smith, Allan D Hess, James M Foran, Judith E Karp, Scott H Kaufmann
: : Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples...
November 7, 2016: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/27815049/therapeutic-effects-of-a-nedd8-activating-enzyme-inhibitor-pevonedistat-on-sclerodermatous-graft-versus-host-disease-in-mice
#3
Chien-Chun Steven Pai, Lam T Khuat, Mingyi Chen, William J Murphy, Mehrdad Abedi
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the ultimate treatment for highly malignant hematologic disease; however, the major complication-graft-versus-host disease (GVHD)-still hinders its clinical application. In addition, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HSCT. Previously we showed that bortezomib, a proteasome inhibitor, can ameliorate the sclerodermatous GVHD response while maintaining graft-versus-tumor (GVT) effects. Here we report that pevonedistat (MLN4924), an inhibitor of the Nedd8-activating enzyme, which functions upstream of the proteasome in the ubiquitin-proteasome pathway, can also show similar protective effects...
November 1, 2016: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/27810909/the-ubiquitin-ligase-crl2zyg11-targets-cyclin-b1-for-degradation-in-a-conserved-pathway-that-facilitates-mitotic-slippage
#4
Riju S Balachandran, Cassandra S Heighington, Natalia G Starostina, James W Anderson, David L Owen, Srividya Vasudevan, Edward T Kipreos
The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase is known to target the degradation of cyclin B1, which is crucial for mitotic progression in animal cells. In this study, we show that the ubiquitin ligase CRL2(ZYG-11) redundantly targets the degradation of cyclin B1 in Caenorhabditis elegans and human cells. In C. elegans, both CRL2(ZYG-11) and APC/C are required for proper progression through meiotic divisions. In human cells, inactivation of CRL2(ZYG11A/B) has minimal effects on mitotic progression when APC/C is active...
October 24, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27783255/targeting-the-protein-ubiquitination-machinery-in-melanoma-by-the-nedd8-activating-enzyme-inhibitor-pevonedistat-mln4924
#5
Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27780719/prostate-cancer-associated-mutation-in-spop-impairs-its-ability-to-target-cdc20-for-poly-ubiquitination-and-degradation
#6
Fei Wu, Xiangpeng Dai, Wenjian Gan, Lixin Wan, Min Li, Nicholas Mitsiades, Wenyi Wei, Qiang Ding, Jinfang Zhang
Recent studies revealed that mutations in SPOP (Speckle-type POZ protein) occur in up to 15% of patients with prostate cancer. However, the physiological role of SPOP in regulating prostate tumorigenesis remains elusive. Here, we identified the Cdc20 oncoprotein as a novel ubiquitin substrate of SPOP. As such, pharmacological inhibition of Cullin-based E3 ligases by MLN4924 could stabilize endogenous Cdc20 in cells. Furthermore, we found that Cullin 3, and, to a less extent, Cullin 1, specifically interacted with Cdc20...
October 22, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27771247/an-inhibitor-of-apoptosis-protein-antagonist-t-3256336-potentiates-the-antitumor-efficacy-of-the-nedd8-activating-enzyme-inhibitor-pevonedistat-tak-924-mln4924
#7
Hiroyuki Sumi, Masakazu Inazuka, Megumi Morimoto, Ryosuke Hibino, Kentaro Hashimoto, Tomoyasu Ishikawa, Keisuke Kuida, Peter G Smith, Sei Yoshida, Masato Yabuki
Inhibitors of apoptosis proteins (IAPs) are antiapoptotic regulators that block cell death, and are frequently overexpressed in several human cancers, where they facilitate evasion of apoptosis and promote cell survival. IAP antagonists are also known as second mitochondria-derived activator of caspase (SMAC)-mimetics, and have recently been considered as novel therapeutic agents for inducing apoptosis, alone and in combination with other anticancer drugs. In this study, we showed that T-3256336, the orally available IAP antagonist has synergistically enhances the antiproliferative effects of the NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924), and these effects were attenuated by a TNFα-neutralizing antibody...
October 19, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27682585/perturbation-of-neddylation-dependent-nf-%C3%AE%C2%BAb-responses-in-the-intestinal-epithelium-drives-apoptosis-and-inhibits-resolution-of-mucosal-inflammation
#8
Stefan F Ehrentraut, Valerie F Curtis, Ruth X Wang, Bejan J Saeedi, Heidi Ehrentraut, Joseph C Onyiah, Caleb J Kelly, Eric L Campbell, Louise E Glover, Douglas J Kominsky, Sean P Colgan
Recent work has revealed a central role for neddylation (the conjugation of a Nedd8-moiety to Cullin proteins) in the fine tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel western blot, luciferase reporter and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB...
September 28, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27602774/circadian-clock-components-ror%C3%AE-and-bmal1-mediate-the-anti-proliferative-effect-of-mln4924-in-osteosarcoma-cells
#9
Shuju Zhang, Jiaming Zhang, Zhiyuan Deng, Huadie Liu, Wei Mao, Fang Jiang, Zanxian Xia, Jia-Da Li
The anticancer small molecule MLN4924, a Nedd8-activating enzyme (NAE) inhibitor, triggers cell-cycle arrest, apoptosis, and senescence in cancer cells. In this study, we demonstrate that MLN4924 suppresses osteosarcoma cell proliferation by inducing G2/M cell cycle arrest and apoptosis. Our results indicate that MLN4924 stabilizes the retinoid orphan nuclear receptor alpha (RORα) by decreasing its ubiquitination. RNA interference of RORα attenuates the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells...
September 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27593482/neddylation-is-required-for-herpes-simplex-virus-type-i-hsv-1-induced-early-phase-interferon-beta-production
#10
Xueying Zhang, Zhenjie Ye, Yujun Pei, Guihua Qiu, Qingyang Wang, Yunlu Xu, Beifen Shen, Jiyan Zhang
Type I interferons such as interferon-beta (IFN-β) play essential roles in the host innate immune response to herpes simplex virus type I (HSV-1) infection. The transcription of type I interferon genes is controlled by nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) family members including IRF3. NF-κB activation depends on the phosphorylation of inhibitor of κB (IκB), which triggers its ubiqitination and degradation. It has been reported that neddylation inhibition by a pharmacological agent MLN4924 potently suppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production with the accumulation of phosphorylated IκBα...
September 2016: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/27543965/sag-rbx2-dependent-neddylation-regulates-t-cell-responses
#11
Nathan D Mathewson, Hideaki Fujiwara, Shin-Rong Wu, Tomomi Toubai, Katherine Oravecz-Wilson, Yaping Sun, Corinne Rossi, Cynthia Zajac, Yi Sun, Pavan Reddy
Neddylation is a crucial post-translational modification that depends on the E3 cullin ring ligase (CRL). The E2-adapter component of the CRL, sensitive to apoptosis gene (SAG), is critical for the function of CRL-mediated ubiquitination; thus, the deletion of SAG regulates neddylation. We examined the role of SAG-dependent neddylation in T-cell-mediated immunity using multiple approaches: a novel T-cell-specific, SAG genetic knockout (KO) and chemical inhibition with small-molecule MLN4924. The KO animals were viable and showed phenotypically normal mature T-cell development...
October 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/27528738/correction-the-nedd8-activating-enzyme-inhibitor-mln4924-thwarts-microenvironment-driven-nf-%C3%AE%C2%BAb-activation-and-induces-apoptosis-in-chronic-lymphocytic-leukemia-b-cells
#12
(no author information available yet)
No abstract text is available yet for this article.
August 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27460548/hiv-1-vpr-increases-hcv-replication-through-vprbp-in-cell-culture
#13
Yanling Yan, Fang Huang, Ting Yuan, Binlian Sun, Rongge Yang
Coinfection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) occurs at a high frequency, in which HIV shows a promotion of HCV-derived liver diseases. However, the mechanism of how this occurs is not well understood. Our previous work has demonstrated that the HIV-1 accessory protein Vpr enhances HCV RNA replication in cell culture. Because Vpr performs most of its functions through host protein VprBP (DCAF1), the role of VprBP in the regulation of HCV by Vpr was investigated in this study...
September 2, 2016: Virus Research
https://www.readbyqxmd.com/read/27388524/corrigendum-to-the-mln4924-inhibitor-exerts-a-neuroprotective-effect-against-oxidative-stress-injury-via-nrf2-protein-accumulation-redox-biol-8-2016-341-347
#14
A C Andérica-Romero, J Hernández-Damián, G I Vázquez-Cervantes, I Torres, Irma Gabriela González-Herrera, J Pedraza-Chaverri
No abstract text is available yet for this article.
July 4, 2016: Redox Biology
https://www.readbyqxmd.com/read/27333051/inactivation-of-the-crl4-cdt2-set8-p21-ubiquitylation-and-degradation-axis-underlies-the-therapeutic-efficacy-of-pevonedistat-in-melanoma
#15
Mouadh Benamar, Fadila Guessous, Kangping Du, Patrick Corbett, Joseph Obeid, Daniel Gioeli, Craig L Slingluff, Tarek Abbas
UNLABELLED: The cullin-based CRL4-CDT2 ubiquitin ligase is emerging as a master regulator of cell proliferation. CRL4-CDT2 prevents re-initiation of DNA replication during the same cell cycle "rereplication" through targeted degradation of CDT1, SET8 and p21 during S-phase of the cell cycle. We show that CDT2 is overexpressed in cutaneous melanoma and predicts poor overall and disease-free survival. CDT2 ablation inhibited a panel of melanoma cell lines through the induction of SET8- and p21-dependent DNA rereplication and senescence...
August 2016: EBioMedicine
https://www.readbyqxmd.com/read/27224919/radiosensitization-by-the-investigational-nedd8-activating-enzyme-inhibitor-mln4924-pevonedistat-in-hormone-resistant-prostate-cancer-cells
#16
Xiaofang Wang, Wenjuan Zhang, Zi Yan, Yupei Liang, Lihui Li, Xiaoli Yu, Yan Feng, Shen Fu, Yanmei Zhang, Hu Zhao, Jinha Yu, Lak Shin Jeong, Xiaomao Guo, Lijun Jia
Salvage radiotherapy (SRT) is the first-line treatment for prostate cancer patients with biochemical recurrence following radical prostatectomy, and new specific radiosensitizers are in urgent need to enhance SRT effect. MLN4924 (also known as Pevonedistat), a specific inhibitor of NEDD8-activating enzyme, has recently entered phase I/II clinical trials in several malignancies. By inhibiting cullin neddylation, MLN4924 inactivates Cullin-RING ligases (CRL), which have been validated as an attractive radiosensitizing target...
May 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27223074/mln4924-suppresses-neddylation-and-induces-cell-cycle-arrest-senescence-and-apoptosis-in-human-osteosarcoma
#17
Yi Zhang, Cheng-Cheng Shi, Hua-Peng Zhang, Gong-Quan Li, Shan-Shan Li
Neddylation is a post-translational protein modification process associated with carcinogenesis and cancer development. MLN4924, a pharmaceutical neddylation inhibitor, induces potent anti-cancer effects in multiple types of cancers. In this study, we investigated the effects of MLN4924 on human osteosarcoma (OS). Levels of both NEDD8 activating enzyme E1 (NAE1) and ubiquitin-conjugating enzyme E2M (Ube2M), two critical components of the neddylation pathway, were much higher in OS tissues and cells than in normal osseous tissues and cells...
May 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27162365/blockage-of-neddylation-modification-stimulates-tumor-sphere-formation-in-vitro-and-stem-cell-differentiation-and-wound-healing-in-vivo
#18
Xiaochen Zhou, Mingjia Tan, Mukesh K Nyati, Yongchao Zhao, Gongxian Wang, Yi Sun
MLN4924, also known as pevonedistat, is the first-in-class inhibitor of NEDD8-activating enzyme, which blocks the entire neddylation modification of proteins. Previous preclinical studies and current clinical trials have been exclusively focused on its anticancer property. Unexpectedly, we show here, to our knowledge for the first time, that MLN4924, when applied at nanomolar concentrations, significantly stimulates in vitro tumor sphere formation and in vivo tumorigenesis and differentiation of human cancer cells and mouse embryonic stem cells...
May 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27063292/neddylation-inhibitor-mln4924-suppresses-growth-and-migration-of-human-gastric-cancer-cells
#19
Huiyin Lan, Zaiming Tang, Hongchuan Jin, Yi Sun
MLN4924 is a recently discovered small molecule inhibitor of NEDD8-Activating Enzyme (NAE). Because cullin RING ligase (CRL), the largest family of E3 ubiquitin ligase, requires cullin neddylation for its activity, MLN4924, therefore, acts as an indirect inhibitor of CRL by blocking cullin neddylation. Given that CRLs components are up-regulated, whereas neddylation modification is over-activated in a number of human cancers, MLN4924 was found to be effective in growth suppression of cancer cells. Whether MLN4924 is effective against gastric cancer cells, however, remains elusive...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27056178/a-phase-i-study-of-the-investigational-nedd8-activating-enzyme-inhibitor-pevonedistat-tak-924-mln4924-in-patients-with-metastatic-melanoma
#20
Shailender Bhatia, Anna C Pavlick, Peter Boasberg, John A Thompson, George Mulligan, Michael D Pickard, Hélène Faessel, Bruce J Dezube, Omid Hamid
Purpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles...
August 2016: Investigational New Drugs
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