A5026859151- X-ray Diffraction in Crystallography
- Protein Degradation and Inhibitors
- Crystallization and Solubility Studies
- Enzyme Structure and Function
- Ubiquitin and proteasome pathways
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
- Heat shock proteins research
- Viral Infectious Diseases and Gene Expression in Insects
- Protein Kinase Regulation and GTPase Signaling
- Advanced Biosensing Techniques and Applications
- Advanced Fluorescence Microscopy Techniques
- Chemical Synthesis and Analysis
- HER2/EGFR in Cancer Research
- Chronic Myeloid Leukemia Treatments
- Melanoma and MAPK Pathways
- CAR-T cell therapy research
- Click Chemistry and Applications
- Pharmacogenetics and Drug Metabolism
- thermodynamics and calorimetric analyses
- Nanofabrication and Lithography Techniques
- Microfluidic and Bio-sensing Technologies
- Cytokine Signaling Pathways and Interactions
- Cell death mechanisms and regulation
Takeda (Japan)
2013-2019
Food and Drug Safety Center
2019
The University of Tokyo
2006-2010
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...
Mcl-1 and Bcl-xL are crucial regulators of apoptosis, therefore dual inhibitors both proteins could serve as promising new anticancer drugs. To design Mcl-1/Bcl-xL inhibitors, we performed structure-guided analyses the corresponding selective inhibitors. A cocrystal structure a pyrazolo[1,5-a]pyridine derivative with protein was successfully determined revealed protein–ligand binding mode. The key for inhibition further confirmed through substructural analysis ABT-263, representative...
The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways tumor cells occurs as a result of several types mutational damage, which most frequently affects the amino acids G12, G13, Q61. Recently, KRpep-2d was identified K-Ras(G12D) selective inhibitory peptide against G12D mutant K-Ras, is key member protein family an attractive cancer therapeutic target. In this study, crystal structure human determined complex with...
Cyclin-dependent kinase 12 (CDK12) plays a key role in the coordination of transcription with elongation and mRNA processing. CDK12 mutations found tumors inhibition sensitize cancer cells to DNA-damaging reagents DNA-repair inhibitors. This suggests that inhibitors are potential therapeutics for may cause synthetic lethality. Here, we report discovery 3-benzyl-1-(trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel selective Structure–activity relationship studies...
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...
Owing to their covalent target occupancy, irreversible inhibitors require low exposures and offer long duration, use thus represents a powerful strategy for achieving pharmacological efficacy. Importantly, the potency metric of is kinact/KI not IC50. A simple approach measuring was developed that makes an probe competitive assays run completion against test compounds. In this system, value compound equal (kinact/KI)probe ×[probe]/IC50. The advantages method include simplicity, high...
Controversy exists over whether the chaperonin GroEL forms a GroEL-(GroES)2 complex (football-shaped complex) during its reaction cycle. We have revealed previously existence of football-shaped in cycle using FRET (fluorescence resonance energy transfer) assay [Sameshima, Ueno, Iizuka, Ishii, Terada, Okabe and Funatsu (2008) J. Biol. Chem. 283, 23765-23773]. Although denatured proteins alter ATPase activity dynamics GroEL-GroES interaction, effect on formation has not been characterized. In...
General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under depletion. We initiated studies aiming at discovery novel GCN2 inhibitors as first-in-class antitumor agents conducted modification substructure sulfonamide derivatives with expected type I half binding on GCN2. Our synthetic strategy mainly corresponding to αC-helix allosteric pocket led significant enhancement potency good...
It has been widely believed that an asymmetric GroEL-GroES complex (termed the bullet-shaped complex) is formed solely throughout chaperonin reaction cycle, whereas we have recently revealed a symmetric GroEL-(GroES)2 (the football-shaped can form in presence of denatured proteins. However, dynamics interaction, including complex, unclear. We investigated decay process at single-molecule level. Because submicromolar concentrations fluorescent GroES are required solution to saturated amounts...
B-cell lymphoma 6 (BCL6) is the most frequently involved oncogene in diffuse large lymphomas (DLBCLs). BCL6 shows potent transcriptional repressor activity through interactions with its corepressors, such as corepressor (BCOR). The inhibition of protein–protein interaction (PPI) between and corepressors suppresses growth BCL6-dependent DLBCLs, thus making an attractive drug target for treatment. However, small-molecule PPI inhibitor identification remains challenging because lack deep...
Despite the recent advances in life sciences and remarkable investment drug discovery research, success rate of small-molecule development remains low. Safety is second most influential factor attrition clinical studies; thus, selection compounds with fewer toxicity concerns crucial to increase discovery. Compounds that promiscuously bind multiple targets are likely cause unexpected pharmacological activity may lead adverse effects. Therefore, avoiding such during early research stages would...
In a high-throughput screening (HTS) process, the chemical reactivity of test samples should be carefully examined because such reactive compounds may lead to false-positive results and adverse effects in vivo. Among all natural amino acids, thiol side chain cysteine has highest nucleophilicity; thus, assessment intrinsic group HTS processes is expected accelerate drug discovery. general, kchem (M-1s-1), secondary reaction rate constant compound thiol, can evaluated via time course...
Dysferlinopathies, which are muscular diseases caused by mutations in the dysferlin gene, remain serious medical problems due to lack of therapeutic agents. Herein, we report design, synthesis, and structure-activity relationships a 2,6-disubstituted 3H-imidazo[4,5-b]pyridine series, was identified from phenotypic screening chemicals that increase level myocytes differentiated patient-derived induced pluripotent stem cells (iPSCs). Optimization studies with cell-based assay led...
Recently, there have been a limited number of new, validated targets for small-molecule drug discovery in the pharmaceutical industry. Although are approximately 30 000 genes human genome, only 2% targeted by currently approved drugs. One reason that many remain neglected programs is absence biochemical assays enabling evaluation potency inhibitors quantitative and high-throughput manner. To overcome this issue, we developed assay to evaluate both reversible irreversible using nonspecific...
Abstract Owing to their covalent target occupancy, irreversible inhibitors require low exposures and offer long duration, use thus represents a powerful strategy for achieving pharmacological efficacy. Importantly, the potency metric of is k inact / K I not IC 50 . A simple approach measuring was developed that makes an probe competitive assays run completion against test compounds. In this system, value compound equal ( ) ×[probe]/IC The advantages method include simplicity, high...