A5086235609- Genetic Neurodegenerative Diseases
- Neurological disorders and treatments
- Mitochondrial Function and Pathology
- PI3K/AKT/mTOR signaling in cancer
- Blood Coagulation and Thrombosis Mechanisms
- Aerospace Engineering and Energy Systems
- Protein Kinase Regulation and GTPase Signaling
- Functional Brain Connectivity Studies
- Synthesis and Properties of Aromatic Compounds
- Electromagnetic wave absorption materials
- Guidance and Control Systems
- Pancreatic function and diabetes
- Advanced Antenna and Metasurface Technologies
- Structural Analysis and Optimization
- Metabolism, Diabetes, and Cancer
- Liver physiology and pathology
- Lipoproteins and Cardiovascular Health
- Neuroscience and Neuropharmacology Research
- Biochemical and Molecular Research
- Particle accelerators and beam dynamics
- Mechanical Behavior of Composites
- Synthesis and Reactions of Organic Compounds
- Melanoma and MAPK Pathways
- Chemical Synthesis and Analysis
- Underwater Vehicles and Communication Systems
National University of Defense Technology
2016-2024
East China University of Technology
2024
CHDI Foundation
2019-2023
Shaoxing University
2010-2021
Xiamen University
2021
Amgen (United States)
2008-2020
Shaoxing People's Hospital
2009-2018
Wenzhou Medical University
2016
Zhejiang University
2012-2016
Beihang University
2011-2015
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAn improved procedure for the preparation of Dess-Martin periodinaneRobert E. Ireland and Longbin LiuCite this: J. Org. Chem. 1993, 58, 10, 2899Publication Date (Print):May 1, 1993Publication History Published online1 May 2002Published inissue 1 1993https://pubs.acs.org/doi/10.1021/jo00062a040https://doi.org/10.1021/jo00062a040research-articleACS PublicationsRequest reuse permissionsArticle Views14832Altmetric-Citations599LEARN ABOUT THESE...
KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable yet be identified. Here, we report efforts exploit cryptic pocket (H95/Y96/Q99) identified identify suitable for clinical development. Structure-based design leading identification novel quinazolinone scaffold are described, along with optimization that overcame...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTImproved methodology for photocyclization reactionsLongbin Liu, Bingwei Yang, Thomas J. Katz, and Michael K. PoindexterCite this: Org. Chem. 1991, 56, 12, 3769–3775Publication Date (Print):June 1, 1991Publication History Published online1 May 2002Published inissue 1 June 1991https://pubs.acs.org/doi/10.1021/jo00012a005https://doi.org/10.1021/jo00012a005research-articleACS PublicationsRequest reuse permissionsArticle...
CuI-catalyzed N-arylation of imidazoles with aryl bromides has been achieved in a near-homogeneous system that utilizes tetraethylammonium carbonate as base, 8-hydroxyquinoline ligand, and H2O cosolvent. Preliminary results chlorides are also reported.
There is an unmet need in severe asthma where approximately 40% of patients exhibit poor beta-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists the Ca2+-activated-Cl¯ channel, TMEM16A, offers a new mechanism to bronchodilate airways block multiple contractiles operating disease. To identify TMEM16A antagonists we screened library ~580,000 compounds. The anthelmintics niclosamide, nitazoxanide related compounds were identified as potent that blocked...
Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays key regulatory role in several cellular processes. The mutation or amplification of this humans has been implicated the growth multiple tumor types. Consequently, PI3Kα become target intense research for drug discovery. Our studies began with identification benzothiazole compound 1 from high throughput screen. Extensive SAR led to discovery sulfonamide 45 as an early lead, based on its vitro potency. Subsequent modifications...
Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification activating mutations c-Met, as well MET gene amplification human cancers, points an important target for cancer therapy. We have previously described two classes inhibitors (class I class II) that differ their binding modes selectivity profiles. The II tend activities on multiple kinases. Knowledge mode these molecules protein led design...
Huntington's disease is an autosomal, dominantly inherited neurodegenerative caused by expansion of the CAG repeats in exon 1 huntingtin gene. Neuronal degeneration and dysfunction that precedes regional atrophy result impairment striatal cortical circuits affect brain's large-scale network functionality. However, evolution these disease-driven, connectivity alterations still poorly understood. Here we used resting-state fMRI to investigate functional changes a mouse model several relevant...
Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition over VEGFR2. However, studies revealed generation active, nonselective metabolites. Blocking this metabolic hot spot led to discovery 17 (AMG 458). When dosed orally, significantly inhibited tumor growth NIH3T3/TPR-Met and U-87 MG xenograft models no adverse effect on body weight.
c-Met is a receptor tyrosine kinase that plays key role in several cellular processes but has also been found to be overexpressed and mutated different human cancers. Consequently, targeting this enzyme become an area of intense research drug discovery. Our studies began with the design synthesis novel pyrimidone 7, which was potent inhibitor. Subsequent SAR identified 22 as more analog, whereas X-ray crystal structure 7 bound revealed unexpected binding conformation. This latter finding led...
As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge the binding mode this molecule in both and VEGFR-2 proteins led to novel strategy designing more selective analogues 1. Along with detailed SAR information, we demonstrate that low kinase selectivity...
Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [ 11 C]UCB-J may provide a tool to measure alterations. Given pivotal role mouse models in understanding neuropsychiatric and neurodegenerative this study aims validate characterize mice. We performed blocking verify specificity radiotracer SV2A, examined kinetic an image-derived input function (IDIF) for...
[5]- and [6]helicenebisquinones can be prepared easily in quantity by combining enol ethers of 1,4-diacetylbenzene or 2,7-diacetylnaphthalene with p-benzoquinone. Similar diethenyl aromatics that either have no ether functions them attached not to the double bonds, but aromatic rings, give corresponding helicenes only low yields purities. [6]Helicenebisquinone 11c is resolved into its enantiomers. An X-ray diffraction analysis adduct one these enantiomers l-prolinol shows absolute...
Neuropeptide Y (NPY) has been shown to play an important role in the regulation of food intake and energy balance. Pharmacological data suggests that Y5 receptor subtype contributes effects NPY on appetite, therefore a antagonist might be useful therapeutic agent for treatment obesity. In attempts identify potential antagonists, series pyrrolo[3, 2-d]pyrimidine derivatives was prepared evaluated their ability bind receptors vitro. We report here synthesis initial structure-activity...
The phosphoinositide 3-kinase (PI3K) family catalyzes the ATP-dependent phosphorylation of 3′-hydroxyl group phosphatidylinositols and plays an important role in cell growth survival. There is abundant evidence demonstrating that PI3K signaling dysregulated many human cancers, suggesting therapeutics targeting pathway may have utility for treatment cancer. Our efforts to identify potent, efficacious, orally available PI3K/mammalian target rapamycin (mTOR) dual inhibitors resulted discovery a...
We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of small molecule its endogenous inhibitor, regulatory protein (GKRP). These initial investigations culminated in identification 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), compound that effectively enhanced GK translocation and reduced blood glucose diabetic animals. Herein we report results our...
A highly selective series of inhibitors the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency selectivity, resulting in identification 54 as potent PI3Ks with excellent selectivity over mTOR, related kinases, broad panel protein kinases. Compound demonstrated robust PD–PK relationship inhibiting PI3K/Akt pathway vivo mouse model, it potently inhibited tumor growth...
The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays critical role in important cellular functions such as metabolism, cell growth, and survival. Our efforts identify potent, efficacious, orally available phosphatidylinositol (PI3K) inhibitors potential cancer therapeutics have resulted discovery...
Synaptic dysfunction is a primary mechanism underlying Huntington's Disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A) density by means of <sup>11</sup>C-UCB-J microPET imaging the central nervous system (CNS) HD mice. <b>METHODS:</b> Dynamic was performed at clinically relevant disease stages (at 3, 7, 10, and 16 months, M) heterozygous knock-in Q175DN mouse model WT littermates (<i>n</i> = 16-18/genotype time point). Cerebral analyses were...