A5040306907- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Crystallization and Solubility Studies
- Cholesterol and Lipid Metabolism
- X-ray Diffraction in Crystallography
- Peroxisome Proliferator-Activated Receptors
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Drug Transport and Resistance Mechanisms
- Metallurgical Processes and Thermodynamics
- Biotin and Related Studies
- Cell Adhesion Molecules Research
- Analytical Chemistry and Chromatography
- Metabolism, Diabetes, and Cancer
- Estrogen and related hormone effects
- Retinoids in leukemia and cellular processes
- Click Chemistry and Applications
- Monoclonal and Polyclonal Antibodies Research
- Platelet Disorders and Treatments
- Pharmacological Effects of Natural Compounds
- Pharmacogenetics and Drug Metabolism
- Carbohydrate Chemistry and Synthesis
- Iron and Steelmaking Processes
- Quinazolinone synthesis and applications
- Hormonal Regulation and Hypertension
Tohoku University
2019-2024
The University of Tokyo
2011-2020
Sendai University
2020
Quantitative BioSciences
2020
Target (United States)
2016
Tokushima University
2016
National Institutes of Health
2016
Showa Pharmaceutical University
2016
National Institute of Health Sciences
2010
Unitika (Japan)
2005-2009
Induction of selective degradation target proteins by small molecules (protein knockdown) would be useful for biological research and treatment various diseases. To achieve protein knockdown, we utilized the ubiquitin ligase activity cellular inhibitor apoptosis 1 (cIAP1), which is activated methyl bestatin (MeBS, 2). We speculated that formation an artificial (nonphysiological) complex cIAP1 a induced hybrid molecule consisting MeBS (2) linked to ligand protein, this lead cIAP1-mediated...
Abstract Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the aggregation of mutant huntingtin (mHtt), and removal toxic mHtt expected to be effective therapeutic approach. We designed two small hybrid molecules ( 1 2 ) linking a ligand for ubiquitin ligase (cellular inhibitor apoptosis protein 1; cIAP1) with probes aggregates, anticipating that these compounds would recruit cIAP1 induce selective degradation ubiquitin‐proteasome system. The synthesized...
While electrophilic reagents for histidine labeling have been developed, we report an umpolung strategy functionalization. A nucleophilic small molecule, 1-methyl-4-arylurazole, selectively labeled under singlet oxygen (1O2) generation conditions. Rapid can be applied instant protein labeling. Utilizing the short diffusion distance of 1O2 and a technique to localize generator, photocatalyst in close proximity ligand-binding site, demonstrated antibody Fc-selective on magnetic beads...
Manipulation of protein stability with small molecules is a challenge in the field drug discovery. Here we show that cellular retinoic acid binding protein-II (CRABP-II) can be specifically degraded by novel compound, SNIPER-4, consisting (−)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-l-leucine methyl ester and all-trans are ligands for inhibitor apoptosis 1 (cIAP1) CRABP-II, respectively. Mechanistic analysis revealed SNIPER-4 induces cIAP1-mediated ubiquitylation resulting proteasomal...
We successfully knocked down HaloTag-fused nuclear proteins in living cells by using protein knockdown technology.
Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series hybrid named SNIPER (specific and nongenetic IAP-dependent protein ERaser) induces the degradation target via ubiquitin-proteasome system. To understand localization can be by this knockdown technology, examined whether are able to induce cellular retinoic acid binding II (CRABP-II) localized subcellular compartments...
The onset of neurodegenerative disorders (NDs), such as Alzheimer's disease, is associated with the accumulation aggregates misfolded proteins. We previously showed that chemical knockdown ND-related aggregation-prone proteins can be achieved by proteolysis targeting chimeras (PROTACs). However, hetero-bifunctional PROTACs generally show poor permeability into central nervous system, where NDs are located. Here, we document conversion one our hydrophobic tags (HyTs), another class degraders...
To obtain novel transrepression-selective liver X receptor (LXR) ligands, we adopted a strategy of reducing the transactivational agonistic activity 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one derivative 10, which exhibits LXR-mediated transrepressional and activity. Structural modification 10 based on reported X-ray crystal structure LXR ligand-binding domain led to series compounds, almost all exhibited at 1 or μM but showed no even 30 μM. Among compounds obtained, 18 22...
Anti-inflammatory effects of liver X receptor (LXR) ligands are thought to be largely due LXR-mediated transrepression, whereas side caused by activation LXR-responsive gene expression (transactivation). Therefore, selective LXR modulators that preferentially exhibit transrepression activity should anti-inflammatory properties with fewer effects. Here, we synthesized a series styrylphenylphthalimide analogues and evaluated their structure–activity relationships focusing on...