A5001523978- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- Peptidase Inhibition and Analysis
- Cholesterol and Lipid Metabolism
- Chronic Myeloid Leukemia Treatments
- Multiple Myeloma Research and Treatments
- Genetically Modified Organisms Research
- RNA Interference and Gene Delivery
- CAR-T cell therapy research
- Plant Virus Research Studies
- Histone Deacetylase Inhibitors Research
- interferon and immune responses
- Cell Adhesion Molecules Research
- Antimicrobial Peptides and Activities
- Atherosclerosis and Cardiovascular Diseases
- Viral Infectious Diseases and Gene Expression in Insects
- PI3K/AKT/mTOR signaling in cancer
- RNA and protein synthesis mechanisms
- Cancer, Lipids, and Metabolism
- Peroxisome Proliferator-Activated Receptors
- Acute Lymphoblastic Leukemia research
- Lipid metabolism and biosynthesis
- melanin and skin pigmentation
- Biochemical Analysis and Sensing Techniques
National Institute of Health Sciences
2016-2025
National Institute of Health Sciences
2022-2024
NTL Institute for Applied Behavioral Science
2022
Target (United States)
2016-2019
Kawasaki Hospital
2019
Tokushima University
2016
National Institutes of Health
2016
Showa Pharmaceutical University
2016
University of California, San Diego
2008-2013
RIKEN
2001-2007
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,...
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...
Squalene epoxidase, a membrane-associated enzyme that converts squalene to 2,3-oxide, plays an important role in the maintenance of cholesterol homeostasis. In 1957, Bloch and colleagues identified factor from rat liver cytosol termed "supernatant protein (SPF)," which promotes epoxidation catalyzed by microsomes with oxygen, NADPH, FAD, phospholipid [Tchen, T. & Bloch, K. (1957) J. Biol. Chem. 226, 921-930]. Although purification SPF 11,000-fold was reported, no information is so far...
25-Hydroxycholesterol (25OHC) is an enzymatically derived oxidation product of cholesterol that modulates lipid metabolism and immunity. 25OHC synthesized in response to interferons exerts broad antiviral activity by as yet poorly characterized mechanisms. To gain further insights into the basis for activity, we evaluated time-dependent responses macrophage lipidome transcriptome treatment. In addition altering specific aspects sphingolipid metabolism, found activates integrated stress (ISR)...
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...
Targeted protein degradation by proteolysis-targeting chimera (PROTAC) is one of the exciting modalities for drug discovery and biological discovery. It important to select an appropriate linker, E3 ligase ligand, a target ligand in development; however, it necessary synthesize large number PROTACs through trial error. Herein, using docking simulation ternary complex hematopoietic prostaglandin D synthase (H-PGDS) degrader, H-PGDS, cereblon, we have succeeded developing PROTAC(H-PGDS)-7 (6),...
Chemical leukoderma is a disorder induced by chemicals such as rhododendrol and monobenzone. These compounds possess p-substituted phenol moiety undergo oxidation into highly reactive toxic o-quinone metabolites tyrosinase. This metabolic activation plays critical role in the development of through production damage to melanocytes immunological responses. study aimed develop simple method for assessing leukoderma-inducing phenols without analyzing metabolite. Although B16BL6 melanoma cells...