A5062887885- Ubiquitin and proteasome pathways
- Glioma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Prostate Cancer Treatment and Research
- Cancer-related Molecular Pathways
- DNA Repair Mechanisms
- Ovarian cancer diagnosis and treatment
- Cancer Mechanisms and Therapy
- Peptidase Inhibition and Analysis
- Ferroptosis and cancer prognosis
- Microtubule and mitosis dynamics
- Cancer therapeutics and mechanisms
- Histone Deacetylase Inhibitors Research
- Synthesis and Biological Activity
- Acute Myeloid Leukemia Research
- RNA modifications and cancer
- 14-3-3 protein interactions
- Cancer, Hypoxia, and Metabolism
- Autophagy in Disease and Therapy
- Cancer Research and Treatments
- Click Chemistry and Applications
- NF-κB Signaling Pathways
- Mechanisms of cancer metastasis
- Renal cell carcinoma treatment
Takeda (United States)
2008-2024
Millennium Engineering and Integration (United States)
2007-2021
AVEO Oncology (United States)
2015
University of Virginia Health System
2013
Takeda (Japan)
2013
The University of Texas Health Science Center at San Antonio
2013
University of Virginia
2010
AST Products (United States)
2005
Whitehead Institute for Biomedical Research
1996-1999
Massachusetts Institute of Technology
1996-1999
MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which cell proliferation has not been defined, although it accompanied DNA rereplication attendant damage. Here we show stabilization of replication factor Cdt1, substrate cullins 1 4, critical for to trigger inhibit proliferation. Even only hour exposure MLN4924, was sufficient elevate...
Genetically encoded libraries of peptides and oligonucleotides are well suited for the identification ligands many macromolecules. A major drawback these techniques is that resultant subject to degradation by naturally occurring enzymes. Here, a method described uses biologically library D-peptide ligands, which should be resistant proteolytic degradation. In this approach, protein synthesized in D-amino acid configuration used select from phage display expressing random L-amino peptides....
Ebola virions contain a surface transmembrane glycoprotein (GP) that is responsible for binding to target cells and subsequent fusion of the viral host-cell membranes. GP expressed as single-chain precursor posttranslationally processed into disulfide-linked fragments GP1 GP2. The GP2 subunit thought mediate membrane fusion. A soluble fragment ectodomain, lacking fusion-peptide region helix, folds stable, highly helical structure in aqueous solution. Limited proteolysis studies identify...
Cancer cells depend on signals that promote cell cycle progression and prevent programmed death would otherwise result from cumulative, aberrant stress. These activities require the temporally controlled destruction of specific intracellular proteins by ubiquitin-proteasome system (UPS). To a large extent, control points in this process include family E3 ubiquitin ligases called cullin-RING (CRLs). The ligase activity these multicomponent complexes requires modification cullin protein...
Abstract Loss of NEDD8-activating enzyme (NAE) function by siRNA knockdown or inhibition the small molecule NAE inhibitor MLN4924 leads to increased steady-state levels direct Cullin-RING ligase (CRL) substrates preventing their ubiquitination and proteasome-dependent degradation. Many these CRL are involved in cell cycle progression, including a critical DNA replication licensing factor CDT1. Cell analysis asynchronous synchronous cultures after revealed effects on distribution activation...
Ovarian cancer has the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause treatment failure and novel therapeutic strategies are urgently needed. MLN4924 NEDDylation inhibitor currently under investigation in multiple phase I studies. We investigated its anticancer activity cisplatin-sensitive -resistant ovarian models.Cellular sensitivity to MLN4924/cisplatin was determined by measuring viability, clonogenic survival, apoptosis. The effects drug...
TAK-981, a first-in-class small-molecule SUMOylation inhibitor, activates type I interferon signaling to promote antitumor immune responses in mice.
MLN4924 is an investigational small-molecule inhibitor of the NEDD8-activating enzyme (NAE) in phase I clinical trials. NAE inhibition prevents ubiquitination and proteasomal degradation substrates for cullin-RING ubiquitin E3 ligases that support cancer pathophysiology, but genetic determinants conferring sensitivity to are unknown. To address this gap knowledge, we conducted a genome-wide siRNA screen identify genes pathways affect lethality melanoma cells. Of 154 identified, approximately...
Ubiquitin-activating enzyme (UAE or E1) activates ubiquitin via an adenylate intermediate and catalyzes its transfer to a ubiquitin-conjugating (E2). MLN4924 is adenosine sulfamate analogue that was identified as selective, mechanism-based inhibitor of NEDD8-activating (NAE), another E1 enzyme, by forming NEDD8-MLN4924 adduct tightly binds at the active site NAE, novel mechanism termed substrate-assisted inhibition (Brownell, J. E., Sintchak, M. D., Gavin, M., Liao, H., Bruzzese, F. J.,...
The nearly ubiquitous development of chemoresistant disease remains a major obstacle against improving outcomes for patients with ovarian cancer. In this investigation, we evaluated the preclinical activity MLN4924, an investigational inhibitor NEDD8-activating enzyme, in cancer cells. Efficacy MLN4924 both alone and combination platinum was assessed. Overall, single-agent exhibited moderate cell lines. However, cisplatin or carboplatin produced synergistic effects SKOV3 ES2 cells, as well...
Abstract 2-(8-Hydroxy-6-methoxy-1-oxo-1Η-2-benzopyran-3-yl)propionic acid (NM-3) is a small molecule isocoumarin derivative that has recently entered clinical trials as an orally bioavailable anticancer agent. NM-3 induces lethality of human carcinoma cells by both apoptotic and nonapoptotic mechanisms potentiates the effects cytotoxic chemotherapeutic agents. The present studies have evaluated on multiple myeloma (MM) cells. results demonstrate dexamethasone-induced killing...
Abstract TAK-981 is a small molecule inhibitor of the SUMOylation enzyme cascade which currently in Phase I clinical trial (NCT03648372). selectively inhibits activity SUMO activating enzyme, forming covalent adduct between and SUMO, thereby decreasing levels SUMOylated proteins. A central feature pharmacological inhibition production type IFNs immune cells, promoting both innate adaptive responses. demonstrates antitumor activity, including complete regression (CR) some tumors,...
Abstract Clinical results of VELCADE® (bortezomib) For Injection have prompted evaluation other enzymes within the ubiquitin proteasome system (UPS) as druggable targets for human cancer. We identified a first in class investigational drug, TAK-243 (MLN7243), which activating enzyme, UAE (UBA1), an essential cellular enzyme responsible > 99% all ubiquitin. Ubiquitin is involved multiple processes including ubiquitin-dependent protein turnover, cell cycle progression, regulation...