A5107443637- Microtubule and mitosis dynamics
- Quinazolinone synthesis and applications
- Pharmacological Receptor Mechanisms and Effects
- Chemical Synthesis and Analysis
- Receptor Mechanisms and Signaling
- Peroxisome Proliferator-Activated Receptors
- PI3K/AKT/mTOR signaling in cancer
- Microbial Natural Products and Biosynthesis
- Tryptophan and brain disorders
- Stress Responses and Cortisol
- Cancer therapeutics and mechanisms
- Cytokine Signaling Pathways and Interactions
- Inflammatory mediators and NSAID effects
- Ubiquitin and proteasome pathways
- Neuropeptides and Animal Physiology
- Synthetic Organic Chemistry Methods
- Natural product bioactivities and synthesis
- Peptidase Inhibition and Analysis
- Cancer, Lipids, and Metabolism
- Chronic Myeloid Leukemia Treatments
- Liver Disease Diagnosis and Treatment
- Synthesis and Characterization of Heterocyclic Compounds
- Radical Photochemical Reactions
- Epigenetics and DNA Methylation
- Eicosanoids and Hypertension Pharmacology
Kogakuin University
2016-2025
Yasuda Women's University
2022-2025
Okayama University
2012-2024
Kyoto Pharmaceutical University
2024
Bioscience Research
2024
The University of Tokyo
2024
University of Shizuoka
2009-2024
Tohoku University
2024
Osaka International Cancer Institute
2018
Kokugakuin University
2016
The signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for oncology drug development. We identified a N-[2-(1,3,4-oxadiazolyl)]-4-quinolinecarboxamide derivative, STX-0119, as novel STAT3 dimerization inhibitor by virtual screen using customized version the DOCK4 program with crystal structure STAT3. In addition, we used in vitro cell-based assays such luciferase reporter gene assay fluorescence resonance energy transfer-based...
Signal transducer and activator of transcription (STAT) 3, a member family DNA-binding molecules, is potential target in the treatment cancer. The highly phosphorylated STAT3 cancer cells contributes to numerous physiological oncogenic signaling pathways. Furthermore, significant association between glioblastoma multiforme stem-like cell (GBM-SC) development maintenance has been demonstrated recent studies. Previously, we reported novel small molecule inhibitor dimerization, STX-0119, as...
The kinesin spindle protein (KSP) is a mitotic involved in the establishment of functional bipolar during cell division. It considered to be an attractive target for cancer chemotherapy with reduced side effects. Based on natural product scaffold-derived fused indole-based inhibitors and known biphenyl-type KSP inhibitors, various carboline carbazole derivatives were synthesized biologically evaluated. β-Carboline lactam-fused exhibited remarkably potent inhibitory activity arrest...
Kinesin spindle protein Eg5 is a target for anticancer therapies, and small molecule inhibitors of its ATPase activity have been developed. We herein report the first time crystal structure biochemical studies on motor domain in complex with new type allosteric inhibitor. The biphenyl-type inhibitor PVZB1194 binds to α4/α6 pocket 15 Å from ATP-binding pocket, which differs conventional that bind L5/α2/α3 Eg5. Binding involved neck-linker conformation also causes conformational changes around...
Signal transducer and activator of transcription (STAT)3, a member family DNA-binding molecules mediating numerous physiological oncogenic signaling pathways, is novel target in cancer cells which show high phosphorylation STAT3. Recently, we identified small-molecule inhibitor STAT3 dimerization, STX-0119, as therapeutic. We investigated the mechanisms responsible for antitumor activity vitro vivo through biochemical biological assays. Specifically, effects STX-0119 on genes (c-myc, cyclin...
A quinazoline derivative PVHD121 (1a) was shown to have strong antiproliferative activity against various tumor-derived cell lines, including A549 (lung), NCI-H460 HCT116 (colon), MCF7 (breast), PC3 (prostate), and HeLa (cervical) cells with IC50 values from 0.1 0.3 μM. structure–activity relationship (SAR) study at the 2- 4-position of core lead discovery more potent anticancer agents (14, 16, 17, 19, 24, 31). The results an in vitro tubulin polymerization assay fluorescent-based colchicine...
Targeted protein degradation using chimeric small molecules, such as proteolysis-targeting chimeras (PROTACs) and specific nongenetic inhibitors of apoptosis (IAP)-dependent erasers (SNIPERs), has attracted attention a method for degrading intracellular target proteins via the ubiquitin-proteasome system (UPS). These molecules variety that can bind to proteins. However, it is difficult develop degraders in absence suitable small-molecule ligands proteins, transcription factors (TFs)....
We found that 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride (SA4503), a potent and selective sigma 1 receptor agonist, significantly enhanced the cerebral acetylcholine (ACh) release in rat using vivo brain microdialysis technique. Interestingly, significant enhancement of ACh elicited by SA4503 was observed frontal cortex hippocampus, although striatal unchanged. This cortical fully reversed haloperidol, prototype antagonist, or N,...
Cdk5 regulatory associated protein 1-like 1 (CDKAL1) is one of the most reliable risk genes for type 2 diabetes mellitus (T2DM). Because CDKAL1 controls glucose-induced insulin secretion by KATP channel responsiveness and faithful decoding Lys codons to prevent mistranslation in pancreatic β-cells, a rescuer defects expected as new antidiabetes drug. We found that eperisone analogs effectively rescued MiaB-deficient Escherichia coli dual-luciferase reporter gene system (MiaB prokaryotic...
A new series of 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives were found to show potent and selective inhibition platelet-dervied growth factor (PDGF) receptor phosphorylation. In this exploration the structure-activity relationships (SARs) prototype inhibitor KN1022, 4-nitrophenylurea moiety was probed. We that 4-substitution on phenyl ring optimal introduction more than two substituents decreased activities. Bulky enhanced Thiourea analogues also...
Because lysine-specific demethylase 1 (LSD1) regulates the maintenance of cancer stem cell properties, small-molecule inhibitors LSD1 are expected to be useful for treatment several cancers. Reversible with submicromolar inhibitory potency have recently been reported, but their exact binding modes poorly understood. In this study, we synthesized a reported reversible inhibitor, 4-[5-(piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3-yl]benzonitrile, which bears 4-piperidinylmethoxy group,...
Caldorazole (1) was isolated from the marine cyanobacterium Caldora sp. collected on Ishigaki Island, Okinawa, Japan. Its structure determined to be a new polyketide that contained two thiazole rings and an O-methylenolpyruvamide moiety. showed strong cytotoxicity toward tumor cells had been seeded at high density. Cell death induced by 1 in HeLa A431 also observed only presence of glycolysis blocker 2-deoxy-d-glucose (2DG). Co-treatment with 2DG remarkably decreased ATP levels these cells....
trans-2-Phenylcycloproylamine (trans-PCPA) has been used as the scaffold to develop covalent-binding inhibitors against lysine-specific demethylase 1 (LSD1/KDM1A), a therapeutic target for several cancers. However, effects of different structural moieties on inhibitory activity, selectivity, and reactivity these derivatives, including cis isomers, LSD1 its paralogue LSD2/KDM1B are not fully understood. Here we synthesized 65 cis- trans-PCPA derivatives evaluated their activity LSD2. One 7c...
We have previously reported that a series of 4-[4-(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives were potent and selective inhibitors platelet-derived growth factor receptor (PDGFR) phosphorylation demonstrated several biological effects such as suppression neointima formation following balloon injury in rat carotid artery by oral administration. Here, we investigated structure-activity relationships the 6,7-dimethoxyquinazolinyl moiety. In regard to...
Exaggerated or inappropriate signaling by the platelet-derived growth factor receptor (PDGFR) tyrosine kinase has been implicated in a wide variety of diseases. Thus, series piperazinyl quinazoline compounds were identified as potent antagonists PDGFR screening chemical libraries. An optimized analog, CT52923, was shown to be an ATP-competitive inhibitor that exhibited remarkable specificity when tested against other kinases, including all members closely related family. The PDGFRs and stem...
Mast cell stabilizers, including disodium cromoglycate (DSCG), were found to have potential as the agonists of an orphan G protein–coupled receptor, GPR35, although it remains be determined whether GPR35 is expressed in mast cells and involved suppression degranulation. Our purpose this study verify expression clarify how modulates We explored roles using system, a line constitutively expressing rat peritoneal cells, bone marrow–derived cultured cells. Immediate allergic responses assessed...