A5081154325- Computational Drug Discovery Methods
- Cancer, Hypoxia, and Metabolism
- SARS-CoV-2 and COVID-19 Research
- Biochemical and Molecular Research
- COVID-19 Clinical Research Studies
- Amino Acid Enzymes and Metabolism
- Ubiquitin and proteasome pathways
- Epigenetics and DNA Methylation
- bioluminescence and chemiluminescence research
- Cancer-related Molecular Pathways
- Adrenal and Paraganglionic Tumors
- RNA modifications and cancer
- Cell Image Analysis Techniques
- Metabolism, Diabetes, and Cancer
- Glioma Diagnosis and Treatment
- Glycosylation and Glycoproteins Research
- Metabolism and Genetic Disorders
- Enzyme function and inhibition
- Histone Deacetylase Inhibitors Research
- Chronic Lymphocytic Leukemia Research
- Mosquito-borne diseases and control
- Monoclonal and Polyclonal Antibodies Research
- Drug Transport and Resistance Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Pharmacogenetics and Drug Metabolism
National Center for Advancing Translational Sciences
2016-2025
National Institutes of Health
2016-2025
Peking Union Medical College Hospital
2024-2025
Chinese Academy of Medical Sciences & Peking Union Medical College
2024-2025
Nanjing Agricultural University
2025
Shanghai Sunshine Rehabilitation Center
2024
National Clinical Research
2024
Ministry of Education of the People's Republic of China
2024
Air Force Medical University
2023
Xijing Hospital
2023
Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. We show that, in human lung cells, acute increases ROS caused inhibition the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation Cys(358). This PKM2 required to divert glucose flux into pentose phosphate pathway and thereby generate sufficient reducing potential detoxification ROS. Lung cells which endogenous was replaced with Cys(358) Ser(358) oxidation-resistant mutant...
Loss of function mutations in Kelch-like ECH Associated Protein 1 (KEAP1), or gain-of-function nuclear factor erythroid 2-related 2 (NRF2), are common non-small cell lung cancer (NSCLC) and associated with therapeutic resistance. To discover novel NRF2 inhibitors for targeted therapy, we conducted a quantitative high-throughput screen using diverse set ∼400 000 small molecules (Molecular Libraries Small Molecule Repository Library, MLSMR) at the National Center Advancing Translational...
Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemoimmunotherapy, but with relapses treatment, refractory disease is the most common outcome, especially in CLL deletion of chromosome 11q or 17p. In addressing need treatments for relapsed disease, we report identification an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose treatment. Auranofin (Ridaura) approved use treating rheumatoid arthritis, it exhibited preclinical...
Abstract The cell entry of SARS-CoV-2 has emerged as an attractive drug repurposing target for COVID-19. Here we combine genetics and chemical perturbation to demonstrate that ACE2-mediated SARS-Cov CoV-2 requires the surface heparan sulfate (HS) assisting cofactor: ablation genes involved in HS biosynthesis or incubating cells with a mimetic both inhibit Spike-mediated viral entry. We show heparin/HS binds Spike directly, facilitates attachment Spike-bearing particles promote screened...
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) has emphasized the urgency to develop effective therapeutics. Drug repurposing screening is regarded as one most practical and rapid approaches for discovery such 3C-like protease (3CLpro), or main (Mpro) SARS-CoV-2 a valid drug target it specific viral enzyme plays an essential role in replication. We performed quantitative high-throughput (qHTS) 10 755 compounds consisting...
Abstract Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene safe and associated functional improvements in patients autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended approved to allow bilateral administration. Here we report an interim analysis of the single-arm trial investigating safety efficacy binaural five pediatric...
The tumour microenvironment contributes to cancer metastasis and drug resistance. However, most high throughput screening (HTS) assays for discovery use cells grown in monolayers. Here we show that a multilayered culture containing primary human fibroblasts, mesothelial extracellular matrix can be adapted into reliable 384- 1,536-multi-well HTS assay reproduces the ovarian (OvCa) metastatic microenvironment. We validate identified inhibitors secondary vitro vivo biological using three OvCa...
Firefly luciferase (FLuc), an ATP-dependent bioluminescent reporter enzyme, is broadly used in chemical biology and drug discovery assays. PTC124 (Ataluren; (3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid) discovered FLuc-based assay targeting nonsense codon suppression, unusually potent FLuc-inhibitor. Paradoxically, related analogs increase cellular FLuc activity levels by posttranslational stabilization. In this study, we show that inhibition stabilization the result of...
The metabolism of cancer cells is altered to support rapid proliferation. Pharmacological activators a tumor cell specific pyruvate kinase isozyme (PKM2) may be an approach for altering the classic Warburg effect characteristic aberrant in yielding novel antiproliferation strategy. In this manuscript, we detail discovery series substituted N,N′-diarylsulfonamides as PKM2. synthesis numerous analogues and evaluation structure−activity relationships are presented well assessments mechanism...
Deubiquitinases are important components of the protein degradation regulatory network. We report discovery ML364, a small molecule inhibitor deubiquitinase USP2 and its use to interrogate biology putative substrate cyclin D1. ML364 has an IC50 1.1 μm in biochemical assay using internally quenched fluorescent di-ubiquitin substrate. Direct binding was demonstrated microscale thermophoresis. induced increase cellular D1 caused cell cycle arrest as shown Western blottings flow cytometry assays...
SARS-CoV-2 is the viral pathogen causing COVID19 global pandemic. Consequently, much research has gone into development of preclinical assays for discovery new or repurposing FDA-approved therapies. Preventing entry a host cell would be an effective antiviral strategy. One mechanism occurs when spike protein on surface binds to ACE2 receptor followed by cleavage at two cut sites ("priming") that causes conformational change allowing and membrane fusion. TMPRSS2 extracellular protease domain...
While vaccine development will hopefully quell the global pandemic of COVID-19 caused by SARS-CoV-2, small molecule drugs that can effectively control SARS-CoV-2 infection are urgently needed. Here, inhibitors spike (S) mediated cell entry were identified in a high throughput screen an approved library with SARS-S and MERS-S pseudotyped particle assays. We discovered six compounds (cepharanthine, abemaciclib, osimertinib, trimipramine, colforsin, ingenol) to be broad spectrum for...
The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal its COVID-19 drug repurposing campaign - named OpenData with the goal of making across a range SARS-CoV-2 related assays available in real-time. cover wide spectrum life cycle, including both viral and human (host) targets. In total, over 10,000 compounds are being tested full concentration-response ranges from multiple annotated small molecule libraries, approved drug,...
Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address urgent need options, we carried out quantitative high-throughput screen using SARS-CoV-2 cytopathic assay with compound collection 8,810 approved and investigational drugs, mechanism-based bioactive compounds, natural products. Three hundred nineteen compounds anti-SARS-CoV-2 activities were identified confirmed, including 91 drugs 49 drugs. The 230...
Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, no current effective therapy available for locally advanced metastatic ACC. Drug repurposing an emerging approach identifying new indications existing drugs, especially cancers such as The objective of this study was to use quantitative high-throughput screening identify agents with antineoplastic activity against ACC.A 4,292 compounds performed on three ACC cell lines: BD140A, SW-13, NCI-H295R.Twenty-one active were identified,...