A5068582192- Folate and B Vitamins Research
- Protein Degradation and Inhibitors
- Sulfur-Based Synthesis Techniques
- Oxidative Organic Chemistry Reactions
- Chemical Synthesis and Reactions
- Photonic Crystals and Applications
- Drug Transport and Resistance Mechanisms
- Multiple Myeloma Research and Treatments
- Cholesterol and Lipid Metabolism
- Cancer, Hypoxia, and Metabolism
- Synthetic Organic Chemistry Methods
- Radical Photochemical Reactions
- Chemical synthesis and alkaloids
- Histone Deacetylase Inhibitors Research
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Catalytic C–H Functionalization Methods
- Marine Sponges and Natural Products
- Catalytic Cross-Coupling Reactions
- Asymmetric Synthesis and Catalysis
- Synthesis and Catalytic Reactions
- Pickering emulsions and particle stabilization
- Pancreatic function and diabetes
- Computational Drug Discovery Methods
- Electrowetting and Microfluidic Technologies
National Institutes of Health
2015-2023
National Center for Advancing Translational Sciences
2016-2023
Springhouse
2013-2016
Janssen (United States)
2013-2016
National Taiwan University
1997-2007
Korea Advanced Institute of Science and Technology
2003-2007
Urbana University
2001-2005
We report the discovery and medicinal chemistry optimization of a novel series pyrazole-based inhibitors human lactate dehydrogenase (LDH). Utilization quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design multiparameter enabled development compounds with potent enzymatic cell-based inhibition LDH activity. Lead such as 63 exhibit low nM both LDHA LDHB, submicromolar production, glycolysis in MiaPaCa2 pancreatic cancer A673 sarcoma...
Abstract Assessment of the interactions between a drug and its protein target in physiologically relevant cellular environment constitutes major challenge pre-clinical discovery space. The Cellular Thermal Shift Assay (CETSA) enables such an assessment by quantifying changes thermal stability proteins upon ligand binding intact cells. Here, we present development validation homogeneous, standardized, target-independent, high-throughput (384- 1536-well formats) CETSA platform that uses split...
An emulsion encapsulation and shrinkage technique for producing large quantities of colloidally stable clusters microspheres (see Figure) is demonstrated. In spite differences in particle properties interactions, the sequence cluster packings remains same three different systems, suggesting that sphere-packing process can be successfully applied to a wide range colloidal materials.
Photonic balls have been fabricated (see Figure) by field‐enhanced electrospray of an aqueous colloidal suspension. The polystyrene (PS) beads inside the suspension droplets self‐organize into opaline while solvent evaporates. are used as templates for inverse photonic balls, and both types exhibit varying reflection colors depending on diameter reflective index contrast.
A microfluidic device is used to generate uniform emulsion droplets containing monodisperse latex spheres at specific intervals by shearing off the tip of incoming aqueous phase junction two channels (see Figure). The water‐in‐oil emulsions are converted colloidal assemblies slowly removing water from droplets.
Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) possess vital physiological toxicological functions in areas such as CNS, inflammation, metabolic disorders, cancers. Overexpression certain ALDHs (e.g., ALDH1A1) is an important biomarker cancers cancer stem cells (CSCs) indicating potential need identification development small molecule ALDH inhibitors. Herein, a newly designed series quinoline-based analogs ALDH1A1 inhibitors...
Schwannoma tumours typically arise on the eighth cranial nerve and are mostly caused by loss of tumour suppressor Merlin (NF2). There no approved chemotherapies for these surgical removal carries a high risk damage to or other close tissue. New treatments schwannoma NF2-null such as meningioma urgently required. Using combination human primary cells mouse models schwannoma, we have examined role Hippo signalling pathway in driving cell growth. both genetic ablation effectors YAP TAZ well...
Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological toxicological functions in areas such as CNS, metabolic disorders, cancers. Increased ALDH (e.g., ALDH1A1) gene expression catalytic activity are vital biomarkers a number of malignancies cancer stem cells, highlighting the need for identification development small molecule inhibitors. A new series theophylline-based analogs potent ALDH1A1 inhibitors is described. The optimization hits...
Significance Podocyte injury is the hallmark of nephrotic syndrome (NS), a leading cause chronic kidney disease affecting approximately 500 million people. We demonstrate that podocyte endoplasmic reticulum (ER) calcium release channel, type 2 ryanodine receptor (RyR2), undergoes phosphorylation during ER stress. The accelerated efflux due to leaky RyR2 activates cytosolic protease calpain 2, injury. Most importantly, we have identified chemical compound, K201, and biotherapeutic protein,...
Lecithin:cholesterol acyltransferase (LCAT) and LCAT-activating compounds are being investigated as treatments for coronary heart disease (CHD) familial LCAT deficiency (FLD). Herein we report the crystal structure of human in complex with a potent piperidinylpyrazolopyridine activator an acyl intermediate-like inhibitor, revealing active conformation. Unlike other activators, binds exclusively to membrane-binding domain (MBD). Functional studies indicate that compound does not modulate...
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation reduced nicotinamide adenine dinucleotide as final step in glycolytic pathway. Glycolysis plays an important role metabolic plasticity cancer cells and has long been recognized a potential therapeutic target. Thus, potent, selective inhibitors LDH represent attractive approach. However, date, pharmacological agents have failed achieve significant target engagement vivo, possibly because...
Abstract Cancer stem cells (CSCs), representing the root of many solid tumors including ovarian cancer, have been implicated in disease recurrence, metastasis, and therapeutic resistance. Our previous study has demonstrated that CSC subpopulation cancer can be limited by DNA damage-binding protein 2 (DDB2). Here, we maintained via cell dedifferentiation, DDB2 is able to suppress this non-CSC-to-CSC conversion repression ALDH1A1 transcription. Mechanistically, binds gene promoter,...
Abstract Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) have been approved for both frontline and recurrent setting in ovarian cancer with homologous recombination (HR) repair deficiency. However, more than 40% of BRCA1/2-mutated lack the initial response to PARPi treatment, majority those that initially respond eventually develop resistance. Our previous study has demonstrated increased expression aldehyde dehydrogenase 1A1 (ALDH1A1) contributes resistance BRCA2-mutated cells by...
Mosaic patterns of blue, green, and orange colors (see figure) are obtained using a multistep photolithography process. Inverse opal films have been pixellated by this process colloidal crystals as templates, resulting in multicolor patterns. The degree photopolymerization is controlled adjusting the UV exposure time and, thus, refractive color inverse can be modulated.
Aldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation both endogenous and exogenous aldehydes. Increased expression ALDH1A1 has been identified in wide-range human cancer stem cells is associated with relapse poor prognosis, raising potential as therapeutic target. To facilitate quantitative high-throughput screening (qHTS) campaigns for discovery, characterization structure-activity-relationship (SAR) studies small molecule inhibitors...
Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss resident proteins in a process termed exodosis. To identify compounds that attenuate redistribution under pathological conditions, we performed quantitative high-throughput screen using Gaussia luciferase (GLuc)-secreted modulated protein (SERCaMP) assay, which monitors secretion ER-resident triggered by...
Abstract A novel method of fabricating multifaceted and nanobored particle arrays via colloidal lithography using colloidal‐crystal layers as masks for anisotropic reactive‐ion etching (RIE) is reported. The shape the sculpted particles dependent on crystal orientation relative to etchant flow, number layers, RIE conditions, matrix (or mask) structure in lithography. Arrays non‐spherical with shapes, which date could not otherwise be produced, are fabricated a tilted process layer‐by‐layer...
Triply periodic diamond, cubic, and gyroid structures are studied as templates for the fabrication of 3D photonic crystals (see figure). The achievable backfilling volume fraction bandgap properties analyzed by considering pinch-off level surfaces. conformal coating on such is found to result in incomplete filling loss bandgap. An attempt solve this problem made using electrophoretic deposition, which results a nearly completely filled titania structure. Supporting information article...
By the promotion of samarium diiodide, thiophene-2-carboxylate reacted with 2 equiv ketones at C-4 and C-5 positions to give diols such as 9. Because intermediary organosamarium species were oxophilic but not too basic, double hydroxyalkylations various ketone substrates, including alkyl aryl ketones, acetylthiophenes, cyclohexanone, α-tetralone, α-phenylacetophenones, realized without complication side reactions. The diol products underwent an acid-catalyzed dehydration dienes 3 10, which...
Adult T-cell leukemia/lymphoma (ATL) is an aggressive lymphoproliferative malignancy caused by human leukemia virus type 1 (HTLV-1). ATL orphan disease with no curative drug treatment regimens urgently needing new combination therapy. HTLV-1-infected cells rely on viral proteins, Tax and HBZ (HTLV-1-b-ZIP factor), to activate the transcription of various host genes that are critical for promoting leukemic transformation. Inhibition bromodomain extraterminal motif (BET) protein was previously...
By the assistance of an N-sulfonyl group or a cyano at C-2 position, hydroxyalkylations indole-3-carbonyls were achieved by promotion samarium diiodide. The indolecarbonyl coupling reactions proceeded in high stereoselectivity via chelate transition states. Intramolecular couplings 1-(3-oxopropyl)indole-3-carboxaldehydes realized as was more reactive toward SmI2 than aliphatic carbonyl group. Elaboration products with oxidizing agents, acid, phosphorus pentasulfide (or Lawesson's reagent),...
Multiscale nanopatterns fabricated by colloidal lithography, using two-dimensional self-assemblies of photoresist particles as masks, are presented. The masks with features multiple length scales obtained photolithography and used for constructing submicrometer-hole arrays over large areas (see Figure). By depositing functional materials through these nanopatterned substrates useful in a wide range applications can be produced.