A5006581729- Ion Channels and Receptors
- Pain Mechanisms and Treatments
- Heat shock proteins research
- Phytochemicals and Antioxidant Activities
- Ion channel regulation and function
- Biochemical Analysis and Sensing Techniques
- Protein Kinase Regulation and GTPase Signaling
- Herbal Medicine Research Studies
- Neurobiology and Insect Physiology Research
- Computational Drug Discovery Methods
- Cholinesterase and Neurodegenerative Diseases
- Alzheimer's disease research and treatments
- Toxin Mechanisms and Immunotoxins
- RNA and protein synthesis mechanisms
- Bioactive Compounds and Antitumor Agents
- PI3K/AKT/mTOR signaling in cancer
- Protein Structure and Dynamics
- Receptor Mechanisms and Signaling
- ATP Synthase and ATPases Research
- Neurogenesis and neuroplasticity mechanisms
- Drug Transport and Resistance Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Phosphodiesterase function and regulation
- Genetics, Aging, and Longevity in Model Organisms
- Biochemical Acid Research Studies
Seoul National University
2016-2025
Korea University
2024
Korea University Medical Center
2024
Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients.Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval use, primarily due issues such as induction heat shock response (HSR), off-target effects, and unfavorable toxicity profiles.We sought examine effects HVH-2930, novel C-terminal inhibitor, overcoming resistance.Methods: The effect HVH-2930 on...
The heat shock protein (Hsp) system plays important roles in cancer stem cell (CSC) and non-CSC populations. However, limited efficacy due to drug resistance toxicity are obstacles clinical use of Hsp90 inhibitors, suggesting the necessity develop novel inhibitors overcoming these limitations.
Abstract Diacylglycerol (DAG) is a versatile lipid whose 1,2- sn -stereoisomer serves both as second messenger in signal transduction pathways that control vital cellular processes, and metabolic precursor for downstream signaling lipids such phosphatidic acid. Effector proteins translocate to available DAG pools the membranes by using conserved homology 1 (C1) domains DAG-sensing modules. Yet, how C1 recognize capture complex environment of biological membrane has remained unresolved 40...
Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer more effective safer alternative to single-target analgesics enhancing efficacy, reducing side effects, minimizing tolerance. This study aimed identify novel multitarget analgesic with improved pharmacological properties. Methods: An in vivo-guided screening approach was used discover new compound. Compound 29, derived from scaffold inspired opiranserin...
Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating N-terminal pyroglutamate β-amyloid peptides (pGlu-Aβ) and thus may participate pathogenesis Alzheimer's disease (AD). We designed a library glutamyl inhibitors based on proposed binding mode preferred substrate, Aβ3E-42. An vitro structure-activity relationship study identified several excellent QC demonstrating 5- to 40-fold increases potency compared known inhibitor. When tested mouse models...
Abstract Despite recent advances, there remains a significant unmet need for the development of new targeted therapies triple-negative breast cancer (TNBC). Although heat shock protein HSP90 is promising target, previous inhibitors have had issues during including undesirable induction response (HSR) and off-target effects leading to toxicity. SL-145 novel, rationally-designed C-terminal inhibitor that induces apoptosis in TNBC cells via suppression oncogenic AKT, MEK/ERK, JAK2/STAT3...
We developed an orally active and blood-brain-barrier-permeable benzofuran analogue (8, MDR-1339) with potent antiaggregation activity. Compound 8 restored cellular viability from Aβ-induced cytotoxicity but also improved the learning memory function of AD model mice by reducing Aβ aggregates in brains. Given high bioavailability brain permeability demonstrated our pharmacokinetic studies, will provide a novel scaffold for Aβ-aggregation inhibitor that may offer alternative treatment AD.
Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe scaled-up synthesis characterization in mouse models of a novel, vanilloid. Potent analgesic activity was observed neuropathic pain, compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to negative assays genotoxicity.
Pain management remains a major challenge in medicine, highlighting the need for development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid (TRPV1) are ion channels that play key roles pain perception. Targeting both TRPA1 TRPV1 simultaneously with dual antagonists offers promising approach to relief. In this study, we investigated series hybrid analogs discover novel agents pain. Among these compounds synthesized by condensation reaction forming...
Abstract Despite the development of advanced therapeutic regimens such as molecular targeted therapy and immunotherapy, 5-year survival patients with lung cancer is still less than 20%, suggesting need to develop additional treatment strategies. The chaperone heat shock protein 90 (Hsp90) plays important roles in maturation oncogenic proteins thus has been considered an anticancer target. Here we show efficacy biological mechanism a Hsp90 inhibitor NCT-50, novobiocin-deguelin analog...
Abstract Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained generation PKC isozyme-specific modulators acting via C1 domain, binding site for lipid second messenger diacylglycerol (DAG) phorbol ester tumor promoters. Synthetic efforts had recently led to identification AJH-836, a DAG-lactone with preferential affinity novel isozymes (nPKCs) relative classical PKCs (cPKCs). Here, we compared ability...
Diacylglycerol (DAG) is a key lipid second messenger downstream of cellular receptors that binds to the C1 domain in many regulatory proteins. Protein kinase C (PKC) isoforms constitute most prominent family signaling proteins with DAG-responsive domains, but six other families proteins, including chimaerins, Ras-guanyl nucleotide-releasing (RasGRPs), and Munc13 isoforms, also play important roles. Their significant involvement cancer, immunology, neurobiology has driven intense interest as...
N-terminal HSP90 inhibitors in development have had issues arising from heat shock response (HSR) induction and off-target effects. We sought to investigate the capacity of NCT-58, a rationally-synthesized C-terminal inhibitor, kill trastuzumab-resistant HER2-positive breast cancer stem-like cells. NCT-58 does not induce HSR due its targeting region elicits anti-tumor activity via simultaneous downregulation HER family members as well inhibition Akt phosphorylation. kills rapidly...
Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there a call for alternative approaches to tackle the multifaceted aspects AD. Among potential targets, we aim focus on glutaminyl cyclase (QC), which reduces toxic pyroform β-amyloid in brains AD patients. On basis putative active conformation prototype inhibitor 1, series N-substituted thiourea, urea, and α-substituted...