A5055913661- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Multiple Myeloma Research and Treatments
- Endoplasmic Reticulum Stress and Disease
- RNA Interference and Gene Delivery
- CAR-T cell therapy research
- Chemical Synthesis and Analysis
- Advanced biosensing and bioanalysis techniques
- Chronic Myeloid Leukemia Treatments
- Histone Deacetylase Inhibitors Research
- Peroxisome Proliferator-Activated Receptors
- Antimicrobial Peptides and Activities
- Cholesterol and Lipid Metabolism
- Microtubule and mitosis dynamics
- Viral Infections and Immunology Research
- Estrogen and related hormone effects
- Viral Infectious Diseases and Gene Expression in Insects
- Drug Transport and Resistance Mechanisms
- Retinoids in leukemia and cellular processes
- interferon and immune responses
- Computational Drug Discovery Methods
- Autophagy in Disease and Therapy
- Biochemical and Structural Characterization
- Lipid metabolism and biosynthesis
National Institute of Health Sciences
2016-2025
Target (United States)
2016-2019
Showa Pharmaceutical University
2016
Tokushima University
2016
National Institutes of Health
2016
The University of Tokyo
2008-2012
Nagoya City University
2003-2010
Many diseases, especially cancers, result from aberrant or overexpression of pathogenic proteins. Specific inhibitors against these proteins have shown remarkable therapeutic effects, but are limited mainly to enzymes. An alternative approach that may utility in drug development relies on selective degradation via small chimeric molecules linking an E3 ubiquitin ligase the targeted protein for proteasomal degradation. To this end, we recently developed a knockdown system based hybrid...
Targeted protein degradation using small molecules is a novel strategy for drug development. We have developed hybrid named specific and nongenetic inhibitor of apoptosis [IAP]-dependent erasers (SNIPERs) that recruit IAP ubiquitin ligases to degrade target proteins. Here, we show SNIPERs capable inducing proteasomal the androgen receptor (AR). Through derivatization SNIPER(AR) molecule at AR ligand linker, 42a (SNIPER(AR)-51), which shows effective knockdown activity against AR. Consistent...
Manipulation of protein stability with small molecules has a great potential for both basic research and clinical therapy. Recently, we have developed series hybrid named SNIPER (Specific Non-genetic IAP-dependent Protein ERaser) that induces degradation target proteins via ubiquitin-proteasome system. Here report the activities SNIPER(ER) targets estrogen receptor alpha (ERα) degradation. induced ERα inhibited estrogen-dependent expression pS2 gene in an breast cancer cell line MCF-7. A...
Abstract The selective degradation of target proteins with small molecules is a novel approach to the treatment various diseases, including cancer. We have developed protein knockdown system series hybrid compounds that induce via ubiquitin–proteasome pathway. In this study, we designed and synthesized called SNIPER(TACC3)s, which spindle regulatory transforming acidic coiled-coil-3 (TACC3). SNIPER(TACC3)s poly-ubiquitylation proteasomal TACC3 reduce level in cells. Mechanistic analysis...
Protein degradation technology based on hybrid small molecules is an emerging drug modality that has significant potential in discovery and as a unique method of post-translational protein knockdown the field chemical biology. Here, we report first example novel potent inducer binds to allosteric site oncogenic BCR-ABL protein. ligands were incorporated into SNIPER (Specific Nongenetic inhibitor apoptosis [IAP]-dependent Erasers) platform, series vitro biological assays binding affinity,...
Targeted protein degradation using chimeric small molecules such as proteolysis-targeting chimeras (PROTACs) and specific nongenetic inhibitors of apoptosis [IAP]-dependent erasers (SNIPERs) is an emerging modality in drug discovery. Here, we expand the repertoire E3 ligases capable ubiquitylating target proteins this system. By incorporating β-naphthoflavone (β-NF) a ligand, developed novel class that recruit arylhydrocarbon receptor (AhR) ligase complex. β-NF-ATRA, degrader directed...
Chromosomal translocation occurs in some cancer cells, which results the expression of aberrant oncogenic fusion proteins that include BCR ‐ ABL chronic myelogenous leukemia ( CML ). Inhibitors tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence drug resistance hampers therapy during long‐term treatment. An alternative approach to treat is downregulate protein. We have devised a protein knockdown system by hybrid molecules named...
Bone morphogenetic protein (BMP) signaling regulates many different biological processes, including cell growth, differentiation, and embryogenesis. BMPs bind to heterogeneous complexes of transmembrane serine/threonine (Ser/Thr) kinase receptors known as the BMP type I II (BMPRI BMPRII). BMPRII phosphorylates activates BMPRI kinase, which in turn Smad proteins. The cytoplasmic region contains a "tail" domain (BMPRII-TD) with no enzymatic activity or regulatory function. discovery mutations...
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...
Abstract Cell-penetrating peptides (CPP) are received a lot of attention as an intracellular delivery tool for hydrophilic molecules such drugs, proteins, and DNAs. We designed synthesized nona-arginine analogues 1 – 5 [FAM-β-Ala-( l -Arg- -Pro) 3 -(Gly) -NH 2 ( ), FAM-β-Ala-( -Pro NH2 ) Gu -Arg) -( 4 - 6 )] containing -proline or cationic proline derivatives investigated their cell-penetrating abilities. Interestingly, only peptide having the side-chain guanidinyl exhibited secondary...
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...
Abstract Chronic myelogenous leukemia (CML) is characterized by the oncogenic fusion protein, BCR-ABL protein kinase, against which clinically useful inhibitors have been developed. An alternative approach to treat CML degrade protein. Recently, potent degraders developed conjugating dasatinib ligands for E3 ubiquitin ligases. Since contain moiety, they also inhibit kinase activity, complicates our understanding of impact degradation in growth inhibition. To address this issue, we chose...
Targeted protein degradation by small molecules is an emerging modality with significant potential for drug discovery. We previously developed chimeric molecules, termed specific and non-genetic inhibitor of apoptosis (IAP)-dependent erasers (SNIPERs), which induce the ubiquitylation proteasomal target proteins. This mediated IAPs; proteins include bromodomain-containing 4 (BRD4), epigenetic regulator protein. The SNIPER that degrades this particular protein, SNIPER(BRD)-1, consists IAP...
Kurarinone, a flavonoid isolated from the roots of Sophora flavescens, was suggested to exert potent antioxidant and immunosuppressive effects. However, underlying mechanisms remain unclear. Nuclear factor erythroid 2-related 2 (Nrf2) is key transcription that regulates defense system with anti-inflammatory activity. In present study, we demonstrated kurarinone activated Nrf2 increased expression enzymes, including heme oxygenase-1 (HO-1). Mechanistically, downregulated kelch-like...