A5071916793- Receptor Mechanisms and Signaling
- Cannabis and Cannabinoid Research
- DNA Repair Mechanisms
- RNA modifications and cancer
- Cancer therapeutics and mechanisms
- Cancer-related gene regulation
- Gout, Hyperuricemia, Uric Acid
- Neuroscience and Neuropharmacology Research
- Inflammasome and immune disorders
- Computational Drug Discovery Methods
- Neuropeptides and Animal Physiology
- Heme Oxygenase-1 and Carbon Monoxide
- CRISPR and Genetic Engineering
- Synthesis and biological activity
- Cytomegalovirus and herpesvirus research
- Hippo pathway signaling and YAP/TAZ
- Analytical chemistry methods development
- Protein Degradation and Inhibitors
- SARS-CoV-2 and COVID-19 Research
- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Cancer-related Molecular Pathways
- Sphingolipid Metabolism and Signaling
- Gait Recognition and Analysis
- Histone Deacetylase Inhibitors Research
Sichuan University
2017-2024
State Key Laboratory of Biotherapy
2017-2024
Fujian Medical University
2024
West China Hospital of Sichuan University
2023
South China University of Technology
2020-2023
Chengdu University
2019
Chinese Academy of Sciences
2010-2016
Institute of Applied Ecology
2010-2016
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both which are approved antivirals. All compounds inhibited activity vitro, with 50% inhibitory concentration values ranging 7.6 748.5 nM....
Abstract N6‐methyladenosine (m 6 A) modification, installed by METTL3‐METTL14 complex, is abundant and critical in eukaryotic mRNA. However, its role oral mucosal immunity remains ambiguous. Periodontitis a special but prevalent infectious disease characterized as hyperinflammation of mucosa bone resorption. Here, it reported that genetic deletion Mettl3 alleviates periodontal destruction via suppressing NLRP3 inflammasome activation. Mechanistically, the stability TNFAIP3 (also known A20)...
Recent advances in CRISPR-Cas9 techniques, especially the discovery of base and prime editing, have significantly improved our ability to make precise changes genome. We hypothesized that modulating certain endogenous pathway cells could improve action those editing tools mammalian cells. established a reporter system which small fragment was integrated into genome by (PE). With this system, we screened an in-house small-molecule library identified group histone deacetylase inhibitors...
GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report cryo-electron microscopy (cryo-EM) structure bound with LysoPS (18:1) G i protein, revealing unique ligand recognition mode the negatively charged head group occupying polar cavity formed by TM3, 6 7, hydrophobic tail residing lateral open groove TM3-5. Virtual screening subsequent structural optimization led to...
SET domain bifurcated protein 1 (SETDB1) is a histone lysine methyltransferase that promotes the silencing of some tumour suppressor genes and overexpressed in many cancers. SETDB1 contains unique tandem tudor (TTD) recognizes H3 sequences containing both methylated acetylated lysines. Beginning with identification hit compound (Cpd1), we discovered first potent selective small molecule SETDB1-TTD inhibitor (R,R)-59 through stepwise structure-guided optimization. showed KD value 0.088±0.045...
Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site CB1, activating both Gi β-arrestin signaling pathways. activation diverse pathways could result on-target side effects cannabis addiction, which may hinder potential. A significant challenge pharmacology design a ligand that can modulate specific CB1....
Autophagy inducers represent new promising agents for the treatment of a wide range medical illnesses. However, safe autophagy clinical applications are lacking. Inhibition cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report discovery series containing 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 potent and selective, with an IC50 value 2 nM against...
We herein report the structural optimization and structure–activity relationship studies of 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as a new class receptor-interacting protein kinase 1 (RIPK1) inhibitors. Among all obtained RIPK1 inhibitors, 1-(5-{4-amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2,3-dihydro-1H-indol-1-yl)-2-[3-(trifluoromethoxy)phenyl]ethan-1-one (22b) is most active one. This compound potently inhibited with binding affinity (KD) 0.004...
SIRT6 activation is thought to be a promising target for the treatment of many diseases, particularly cancer. Herein, we report discovery series new small-molecule activators. Structure–activity relationship analyses led identification most potent compound, 2-(1-benzofuran-2-yl)-N-(diphenylmethyl) quinoline-4-carboxamide (12q), which showed an EC1.5 value 0.58 ± 0.12 μM and EC50 5.35 0.69 against SIRT6-dependent peptide deacetylation in FLUOR DE LYS assay. It exhibited weak or no activity...
Abstract N6-methyladenosine (m 6 A) is the most prevalent modification of eukaryotic RNA, which recognized by m A-binding proteins (“readers”) and thereby mediates multiple biological processes. Dysregulation A readers has been linked to various pathologies, but therapeutic potential small molecule inhibitors targeting m6A unknown. Here we report identification characterization a highly potent selective first-in-class inhibitor (YL-5092) YT521-B homology (YTH) domain-containing protein 1...
Selectively targeting the cannabinoid receptor CB2 is an attractive therapeutic strategy for treatment of inflammatory pain without psychiatric side effects mediated by CB1. Herein, we report discovery 4-(1,2,4-oxadiazol-5-yl)azepan-2-one derivatives as a new class agonists. Systematic structure–activity relationship investigations resulted in identification most potent compound 25r. This displayed high selectivity against CB1 (CB2 EC50 = 21.0 nM, Emax 87%, > 30 μM, ratio CB1/CB2 1428) with...
Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying selectivity, which hampers rational design subtype-selective ligands. Herein, we disclose an unusual molecular entropy-driven recognition in cannabinoid (CB) subtypes, revealed through atomic-level dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments....
Pyroptosis, a novel proinflammatory programmed cell death, has been implicated in some ocular diseases. Of special note is the noncanonical pyroptosis that recently recognized to play critical role microbial keratitis. We previously discovered new potent small molecular inhibitor, J114. In this investigation, we will explore whether J114 able inhibit and underlying mechanism. Then lipopolysaccharide (LPS)-induced keratitis mouse model be used evaluate therapeutic effect of vivo.In vitro,...
Ataxia-telangiectasia mutated (ATM) is an atypical serine/threonine protein kinase which implicated in the repair of DNA double-strand breaks. Numerous reports have shown that ATM inhibition attractive target for radiotherapy and chemotherapy sensitization. Herein we report a new series inhibitors containing 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold, was obtained by virtual screening, structural optimization, structure–activity relationship studies. Among inhibitors, A011 one most potent,...
The gonadotrophin-releasing hormone (GnRH) is a central regulator of the human reproductive system and exerts physiological effects by binding to GnRH1R. GnRH–GnRH1R promising therapeutic target for maintenance function. There are several GnRH1R agonists on market, but like GnRH, they all peptide compounds limited their way administration (subcutaneous or intramuscular injection). To date, no published small molecule have been reported. In this paper, HTRF-based screening method has used...