Identifying druggable proteins,which are capable of binding therapeutic compounds,remains a critical and resource-intensive challenge in drug discovery.To address this,we propose CEL-IDP(Comparison of Ensemble Learnin...Identifying druggable proteins,which are capable of binding therapeutic compounds,remains a critical and resource-intensive challenge in drug discovery.To address this,we propose CEL-IDP(Comparison of Ensemble Learning Methods for Identification of Druggable Proteins),a computational framework combining three feature extraction methods Dipeptide Deviation from Expected Mean(DDE),Enhanced Amino Acid Composition(EAAC),and Enhanced Grouped Amino Acid Composition(EGAAC)with ensemble learning strategies(Bagging,Boosting,Stacking)to classify druggable proteins from sequence data.DDE captures dipeptide frequency deviations,EAAC encodes positional amino acid information,and EGAAC groups residues by physicochemical properties to generate discriminative feature vectors.These features were analyzed using ensemble models to overcome the limitations of single classifiers.EGAAC outperformed DDE and EAAC,with Random Forest(Bagging)and XGBoost(Boosting)achieving the highest accuracy of 71.66%,demonstrating superior performance in capturing critical biochemical patterns.Stacking showed intermediate results(68.33%),while EAAC and DDE-based models yielded lower accuracies(56.66%–66.87%).CEL-IDP streamlines large-scale druggability prediction,reduces reliance on costly experimental screening,and aligns with global initiatives like Target 2035 to expand action-able drug targets.This work advances machine learning-driven drug discovery by systematizing feature engineering and ensemble model optimization,providing a scalable workflow to accelerate target identification and validation.展开更多
Objectives:Breast cancer is characterized by significant metabolic dysregulation,in which altered enzyme activity plays a central role.Malate dehydrogenase 2(MDH2),a key enzyme in the tricarboxylic acid cycle,has been...Objectives:Breast cancer is characterized by significant metabolic dysregulation,in which altered enzyme activity plays a central role.Malate dehydrogenase 2(MDH2),a key enzyme in the tricarboxylic acid cycle,has been implicated in several malignancies,but its role in breast cancer tumorigenesis and progression remains unclear.We aimed to elucidate the oncogenic role of MDH2 in breast cancer and to evaluate its potential as a diagnostic,therapeutic,and prognostic biomarker.Methods:We combined in vitro cell-based assays with mouse xenograft models to systematically dissect how MDH2 governs breast cancer growth.In vitro,we assessed the effects of altered MDH2 expression on proliferation,migration,epithelial–mesenchymal transition(EMT),glucose consumption,and adenosine-5′-triphosphate(ATP)production.In vivo,we dynamically monitored tumor growth driven by MDH2 overexpression.Transcriptomic profiling,untargetedmetabolomics,and in-silico druggability analyses were integrated to elucidate downstream mechanisms and therapeutic potential.Results:In vitro,MDH2 depletion suppressed breast cancer cell proliferation and migration,reversed EMT,and markedly reduced glucose consumption and ATP production.In vivo,MDH2 overexpression accelerated xenograft tumor growth.Transcriptomic profiling revealed MDH2 had modified the gene expression profile of breast cancer cells,affecting several metastasis-related genes.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis identified the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB,also known as AKT)pathway as a downstream effector pathway of MDH2.Untargeted metabolomics uncovered 62 MDH2-regulated metabolites,including the immunomodulatory metabolites adenosine and linoleic acid.In-silico modeling confirmed MDH2 as a novel druggable target.Conclusion:Our findings highlight the role of MDH2 in breast cancer metabolism and suggest it as a promising target for cancer therapies targeting metabolism and tumor growth.展开更多
T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malignancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poo...T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malignancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease.In this study,we performed multi-omics integration analysis,which included mRNA expression,chromatin accessibility,and gene-dependency database analyses,to identify potential stage-specific druggable targets and repositioned drugs for this disease.This multi-omics integration helped identify 29 potential pathological genes for T-ALL.These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle,hematopoietic stem cell differentiation,and the AMPK signaling pathway.Of these,four known druggable targets(CDK6,TUBA1A,TUBB,and TYMS)showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL.The TUBA1A expression level was higher in the early T cell precursor(ETP)-ALL cells,while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage.CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naıve to maturation stages.Furthermore,mebendazole and gemcitabine,which target TUBA1A and TYMS,respectively,exerted stage-specific inhibitory effects on T-ALL cell lines,indicating their potential stage-specific antileukemic role in T-ALL.Collectively,our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.展开更多
Autophagy is a critical cellular homeostatic mechanism,and its dysfunction is linked to invasive breast carcinoma(BRCA).Recently,several omics methods have been applied to explore autophagic regulators in BRCA;however...Autophagy is a critical cellular homeostatic mechanism,and its dysfunction is linked to invasive breast carcinoma(BRCA).Recently,several omics methods have been applied to explore autophagic regulators in BRCA;however,more reliable and robust approaches for identifying crucial regulators and druggable targets remain to be discovered.Thus,we report here the results of multi-omics approaches to identify potential autophagic regulators in BRCA,including gene expression(EXP),DNA methylation(MET)and copy number alterations(CNAs)from The Cancer Genome Atlas(TCGA).Newly identified candidate genes,such as SF3 B3,TRAPPC10,SIRT3,MTERFD1,and FBXO5,were confirmed to be involved in the positive or negative regulation of autophagy in BRCA.SF3 B3 was identified firstly as a negative autophagic regulator,and siRNA/shRNA-SF3 B3 were shown to induce autophagyassociated cell death in in vitro and in vivo breast cancer models.Moreover,a novel small-molecule activator of SIRT3,1-methylbenzylamino amiodarone,was discovered to induce autophagy in vitro and in vivo.Together,these results provide multi-omics approaches to identify some key candidate autophagic regulators,such as the negative regulator SF3 B3 and positive regulator SIRT3 in BRCA,and highlight SF3 B3 and SIRT3 as new druggable targets that could be used to fill the gap between autophagy and cancer drug development.展开更多
Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expre...Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expression correlates with TNBC progression in human patients,which promotes TNBC cell proliferation,migration and chemoresistance.Mechanistically,SERCA2 interacts with LC3B via LIR motif,facilitating WIPI2-independent autophagosome formation to induce autophagy.Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca^(2+)/CaMKK/CREB-1 feedback.Moreover,we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death.The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo.This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance,and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.展开更多
This review covers the structures of diterpenoids,including chain(72),monocyclic(9),labdane-type(67),clerodane-type(127)abietane-type(716),ent-kaurane-type(89),grayanane-type(331),ingenanetype(55),tigliane-type(154),d...This review covers the structures of diterpenoids,including chain(72),monocyclic(9),labdane-type(67),clerodane-type(127)abietane-type(716),ent-kaurane-type(89),grayanane-type(331),ingenanetype(55),tigliane-type(154),daphnane-type(237),and aconitine-type diterpene alkaloids(265)with rich biological activities reported in 2013-2023.And the drugs in clinical use or under clinical investigation of diterpenoids and leading compounds were summarized.展开更多
Infection with SARS-COV-2 is the cause of COVID-19 and has generated an unprecedented health crisis worldwide.While most of the patients experience mild symptoms,around 20%develop severe disease,characterized by pneum...Infection with SARS-COV-2 is the cause of COVID-19 and has generated an unprecedented health crisis worldwide.While most of the patients experience mild symptoms,around 20%develop severe disease,characterized by pneumonia and in the worst cases by acute respiratory distress syndrome(ARDS).展开更多
Introduction:There is a renewed interest for thiosemicarbazones in terms of antimicrobial,antiviral,and antitumor activity.With notable exceptions(e.g.thiopental)thiocarbonyl-containing chemical entities are commonly ...Introduction:There is a renewed interest for thiosemicarbazones in terms of antimicrobial,antiviral,and antitumor activity.With notable exceptions(e.g.thiopental)thiocarbonyl-containing chemical entities are commonly considered as non-druggable.Screening of a library of thiosemicarbazones showed,however,exceptional potential.The purpose of this work was both to develop展开更多
Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been...Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.展开更多
SARS-CoV-2(2019-nCoV)emerged in 2019 and proliferated rapidly across the globe.Scientists are attempting to investigate antivirals specific to COVID-19 treatment.The 2019-nCoV and SARS-CoV utilize the same receptor of...SARS-CoV-2(2019-nCoV)emerged in 2019 and proliferated rapidly across the globe.Scientists are attempting to investigate antivirals specific to COVID-19 treatment.The 2019-nCoV and SARS-CoV utilize the same receptor of the host which is COVID-19 of the main protease(Mpro).COVID-19 caused by SARS-CoV-2 is burdensome to overcome by presently acquired antiviral candidates.So the objective and purpose of this work was to investigate the plants with reported potential antiviral activity.With the aid of in silico techniques such as molecular docking and druggability studies,we have proposed several natural active compounds including glycyrrhizin,bicylogermecrene,tryptanthrine,β-sitosterol,indirubin,indican,indigo,hesperetin,crysophanic acid,rhein,berberine andβ-caryophyllene which can be encountered as potential herbal candidate exhibiting anti-viral activity against SARS-CoV-2.Promising docking outcomes have been executed which evidenced the worthy of these selected herbal remedies for future drug development to combat coronavirus disease.展开更多
Objective:To identify novel drug targets for treatment of Plasmodium falciparum.Methods: Local BT.ASTP were used to find the proteins non-homologous to human essential proteins as novel drug targets.Functional domains...Objective:To identify novel drug targets for treatment of Plasmodium falciparum.Methods: Local BT.ASTP were used to find the proteins non-homologous to human essential proteins as novel drug targets.Functional domains of novel drug targets were identified by InterPro and Pfam.3D structures of potential drug targets were predicated by the SWISS-MODEL workspace. Ligands and ligand-binding sites of the proteins were searched by Ef-seek.Results:Three essential proteins were identified that might be considered as potential drug targets.AAN37254.1 belonged to 1-deoxy-D-xylulose 5-phosphate reductoisomerase,CAD50499.1 belonged to chorismale synthase,CAD51220.1 belonged to FAD binging 3 family,but the function of CAD51220.1 was unknown.The 3D structures,ligands and ligand-binding sites of AAM37254.1 and CAD50499.1 were successfully predicated.Conclusions:Two of these potential drug targets are key enzymes in 2-C-methyl-d-erythritol 4-phosphate pathway and shikimate pathway, which are absent in humans,so these two essential proteins are good potential drug targets.The function and 3D structures of CAD50499.1 is still unknown,it still need further study.展开更多
The drug searching for combating the present outbreak of Ebola virus infection is the urgent activity at present.Finding the new effective drug at present must base on the molecular analysis of the pathogenic virus.Th...The drug searching for combating the present outbreak of Ebola virus infection is the urgent activity at present.Finding the new effective drug at present must base on the molecular analysis of the pathogenic virus.The in-depth analysis of the viral protein to find the binding site,active pocket is needed.Here,the authors analyzed the envelope glycoprotein GP2 from Ebola virus.Identification of active pocket and protein draggability within envelope glycoprotein GP2 from Ebola virus was done.According to this assessment,7 active pockets with varied draggability could be identified.展开更多
Natural products are characterized with diverse structures and biological activities. They show a certain degree of adaptability to human beings. However, they need to be modified to increase their druggability. Sever...Natural products are characterized with diverse structures and biological activities. They show a certain degree of adaptability to human beings. However, they need to be modified to increase their druggability. Several strategies including pharmacophore similarity, physicochemical property optimization, and bioactivity focus may help to make them more drug-like candidates.展开更多
In the era of precision oncology,molecular profiling of tumor biopsy or plasma(also known as liquid biopsy)derived from patients with cancer is pivotal in guiding treatment selection.Liquid biopsy allows for the ident...In the era of precision oncology,molecular profiling of tumor biopsy or plasma(also known as liquid biopsy)derived from patients with cancer is pivotal in guiding treatment selection.Liquid biopsy allows for the identification of druggable biomarkers,facilitating optimal cancer care management.1 Non-small cell lung cancer(NSCLC)is at the forefront because of the diverse genetic biomarkers currently approved for guiding targeted therapies.Mesenchymal epithelial transition(MET)is a receptor tyrosine kinase with pleiotropic functions,such as initiating and sustaining neoplastic transformation,driving cancer clonal evolution,and progression toward metastasis after treatment initiation and under therapeutic pressure.2 Exon 14 skipping(METex14skipping)and amplification(METamp)are two important MET dysregulations in NSCLC with distinct oncogenic roles.The concurrent presence of these two MET alterations in patients with NSCLC has rarely been reported,and knowledge of their collective impact on patient response to MET inhibitors such as capmatinib remains elusive.In this paper,we report the case of a 60-year-old woman diagnosed with lung adenocarcinoma and brain metastasis who progressed on first-line(1L)osimertinib treatment with new liver metastasis,along with the outcomes of subsequent testing and treatment management.展开更多
Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S...Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)mice.Besides,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production.Due to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed cells.The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly.By encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,respectively.The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated biotransformation.In summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.展开更多
Inhibitory effect on tumor necrosis factor-c~ （TNF-c0 production by sinomenine derivatives with embedment of small drug-like nitrogen hetereocyclic moieties has been studied in this work. Several new sinomenine deriv...Inhibitory effect on tumor necrosis factor-c~ （TNF-c0 production by sinomenine derivatives with embedment of small drug-like nitrogen hetereocyclic moieties has been studied in this work. Several new sinomenine derivatives having chlorophenyl sub- stituent have been found to exhibit much more potent TNF-a inhibitory activity than natural sinomenine and other derivatives.展开更多
The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections.Herein we discovered novel pyrrolamide-type GyrB/ParE i...The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections.Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AzD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity.The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase(GyrB,IC_(50)=49 nmol/L)and a modest inhibitory effect on TopoⅣ(ParE,IC_(50)=1.513μmol/L)of Staphylococcus aureus.It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration(MIC)of less than 0.03μg/mL,which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S.aureus.Compound 28 had better protective effects than the positive control drugs such as DS-2969(5)and AZD5099(6)in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus(MRSA)infection.It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models.Moreover,compound 28 has much lower mitochondrial toxicity than AZD5099(6)as well as excellent therapeutic indexes and pharmacokinetic properties.At present,compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection.On the other hand,compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli(MIC=1μg/mL),which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently.In addition,the structure-activity relationships of the compounds were also studied.展开更多
基金supported by the MSIT(Ministry of Science and ICT),Korea,under the ITRC(Information Technology Research Centre)support program(IITP-2024-RS-2024-00437191)supervised by the IITP(Institute for Information&Communications Technology Planning&Evaluation).
文摘Identifying druggable proteins,which are capable of binding therapeutic compounds,remains a critical and resource-intensive challenge in drug discovery.To address this,we propose CEL-IDP(Comparison of Ensemble Learning Methods for Identification of Druggable Proteins),a computational framework combining three feature extraction methods Dipeptide Deviation from Expected Mean(DDE),Enhanced Amino Acid Composition(EAAC),and Enhanced Grouped Amino Acid Composition(EGAAC)with ensemble learning strategies(Bagging,Boosting,Stacking)to classify druggable proteins from sequence data.DDE captures dipeptide frequency deviations,EAAC encodes positional amino acid information,and EGAAC groups residues by physicochemical properties to generate discriminative feature vectors.These features were analyzed using ensemble models to overcome the limitations of single classifiers.EGAAC outperformed DDE and EAAC,with Random Forest(Bagging)and XGBoost(Boosting)achieving the highest accuracy of 71.66%,demonstrating superior performance in capturing critical biochemical patterns.Stacking showed intermediate results(68.33%),while EAAC and DDE-based models yielded lower accuracies(56.66%–66.87%).CEL-IDP streamlines large-scale druggability prediction,reduces reliance on costly experimental screening,and aligns with global initiatives like Target 2035 to expand action-able drug targets.This work advances machine learning-driven drug discovery by systematizing feature engineering and ensemble model optimization,providing a scalable workflow to accelerate target identification and validation.
基金supported by grants from the GuangDong Basic and Applied Basic Research Foundation(2023B1515130009)the Science and Technology Bureau of Foshan(No.FS0AA-KJ819-4901-0082).
文摘Objectives:Breast cancer is characterized by significant metabolic dysregulation,in which altered enzyme activity plays a central role.Malate dehydrogenase 2(MDH2),a key enzyme in the tricarboxylic acid cycle,has been implicated in several malignancies,but its role in breast cancer tumorigenesis and progression remains unclear.We aimed to elucidate the oncogenic role of MDH2 in breast cancer and to evaluate its potential as a diagnostic,therapeutic,and prognostic biomarker.Methods:We combined in vitro cell-based assays with mouse xenograft models to systematically dissect how MDH2 governs breast cancer growth.In vitro,we assessed the effects of altered MDH2 expression on proliferation,migration,epithelial–mesenchymal transition(EMT),glucose consumption,and adenosine-5′-triphosphate(ATP)production.In vivo,we dynamically monitored tumor growth driven by MDH2 overexpression.Transcriptomic profiling,untargetedmetabolomics,and in-silico druggability analyses were integrated to elucidate downstream mechanisms and therapeutic potential.Results:In vitro,MDH2 depletion suppressed breast cancer cell proliferation and migration,reversed EMT,and markedly reduced glucose consumption and ATP production.In vivo,MDH2 overexpression accelerated xenograft tumor growth.Transcriptomic profiling revealed MDH2 had modified the gene expression profile of breast cancer cells,affecting several metastasis-related genes.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis identified the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB,also known as AKT)pathway as a downstream effector pathway of MDH2.Untargeted metabolomics uncovered 62 MDH2-regulated metabolites,including the immunomodulatory metabolites adenosine and linoleic acid.In-silico modeling confirmed MDH2 as a novel druggable target.Conclusion:Our findings highlight the role of MDH2 in breast cancer metabolism and suggest it as a promising target for cancer therapies targeting metabolism and tumor growth.
基金the National Natural Science Foundation of China(No.82070167,81870126,81900190,81802803)The Chongqing Science and Technology Bureau Major Project,Chongqing,China(No.cstc2020jcyjmsxmX0782).
文摘T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malignancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease.In this study,we performed multi-omics integration analysis,which included mRNA expression,chromatin accessibility,and gene-dependency database analyses,to identify potential stage-specific druggable targets and repositioned drugs for this disease.This multi-omics integration helped identify 29 potential pathological genes for T-ALL.These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle,hematopoietic stem cell differentiation,and the AMPK signaling pathway.Of these,four known druggable targets(CDK6,TUBA1A,TUBB,and TYMS)showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL.The TUBA1A expression level was higher in the early T cell precursor(ETP)-ALL cells,while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage.CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naıve to maturation stages.Furthermore,mebendazole and gemcitabine,which target TUBA1A and TYMS,respectively,exerted stage-specific inhibitory effects on T-ALL cell lines,indicating their potential stage-specific antileukemic role in T-ALL.Collectively,our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.
基金supported by grants from National Science and Technology Major Project of the Ministry of Science and Technology of the People’s Republic of China(No.2018ZX09735005)National Natural Science Foundation of China(Grant Nos.81522028,81673452,81673455,81873939,81803365 and 81602953)+2 种基金Post-Doctor Research Project(2018M643510,China)Post-Doctor Research Project of West China Hospital,Sichuan University(Grant No.2018HXBH065,China)supported by the grant from“The Recruitment Program of Global Young Experts”(known as“the Thousand Young Talents Plan”,China)。
文摘Autophagy is a critical cellular homeostatic mechanism,and its dysfunction is linked to invasive breast carcinoma(BRCA).Recently,several omics methods have been applied to explore autophagic regulators in BRCA;however,more reliable and robust approaches for identifying crucial regulators and druggable targets remain to be discovered.Thus,we report here the results of multi-omics approaches to identify potential autophagic regulators in BRCA,including gene expression(EXP),DNA methylation(MET)and copy number alterations(CNAs)from The Cancer Genome Atlas(TCGA).Newly identified candidate genes,such as SF3 B3,TRAPPC10,SIRT3,MTERFD1,and FBXO5,were confirmed to be involved in the positive or negative regulation of autophagy in BRCA.SF3 B3 was identified firstly as a negative autophagic regulator,and siRNA/shRNA-SF3 B3 were shown to induce autophagyassociated cell death in in vitro and in vivo breast cancer models.Moreover,a novel small-molecule activator of SIRT3,1-methylbenzylamino amiodarone,was discovered to induce autophagy in vitro and in vivo.Together,these results provide multi-omics approaches to identify some key candidate autophagic regulators,such as the negative regulator SF3 B3 and positive regulator SIRT3 in BRCA,and highlight SF3 B3 and SIRT3 as new druggable targets that could be used to fill the gap between autophagy and cancer drug development.
基金This study was funded by National Natural Science Foundation of China(Nos.21937005 and 81974504)Natural Science Foundation of Jiangsu Province(No.BK 20191251,China)+1 种基金the Fundamental Research Funds for the Central Universities(China)National Key R&D·Program of China(No.2017YFA0506000).
文摘Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expression correlates with TNBC progression in human patients,which promotes TNBC cell proliferation,migration and chemoresistance.Mechanistically,SERCA2 interacts with LC3B via LIR motif,facilitating WIPI2-independent autophagosome formation to induce autophagy.Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca^(2+)/CaMKK/CREB-1 feedback.Moreover,we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death.The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo.This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance,and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.
文摘This review covers the structures of diterpenoids,including chain(72),monocyclic(9),labdane-type(67),clerodane-type(127)abietane-type(716),ent-kaurane-type(89),grayanane-type(331),ingenanetype(55),tigliane-type(154),daphnane-type(237),and aconitine-type diterpene alkaloids(265)with rich biological activities reported in 2013-2023.And the drugs in clinical use or under clinical investigation of diterpenoids and leading compounds were summarized.
文摘Infection with SARS-COV-2 is the cause of COVID-19 and has generated an unprecedented health crisis worldwide.While most of the patients experience mild symptoms,around 20%develop severe disease,characterized by pneumonia and in the worst cases by acute respiratory distress syndrome(ARDS).
文摘Introduction:There is a renewed interest for thiosemicarbazones in terms of antimicrobial,antiviral,and antitumor activity.With notable exceptions(e.g.thiopental)thiocarbonyl-containing chemical entities are commonly considered as non-druggable.Screening of a library of thiosemicarbazones showed,however,exceptional potential.The purpose of this work was both to develop
基金supported by funding from the Bluesand Foundation,Alzheimer's Association(AARG-21-852072 and Bias Frangione Early Career Achievement Award)to EDan Australian Government Research Training Program scholarship and the University of Sydney's Brain and Mind Centre fellowship to AH。
文摘Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.
文摘SARS-CoV-2(2019-nCoV)emerged in 2019 and proliferated rapidly across the globe.Scientists are attempting to investigate antivirals specific to COVID-19 treatment.The 2019-nCoV and SARS-CoV utilize the same receptor of the host which is COVID-19 of the main protease(Mpro).COVID-19 caused by SARS-CoV-2 is burdensome to overcome by presently acquired antiviral candidates.So the objective and purpose of this work was to investigate the plants with reported potential antiviral activity.With the aid of in silico techniques such as molecular docking and druggability studies,we have proposed several natural active compounds including glycyrrhizin,bicylogermecrene,tryptanthrine,β-sitosterol,indirubin,indican,indigo,hesperetin,crysophanic acid,rhein,berberine andβ-caryophyllene which can be encountered as potential herbal candidate exhibiting anti-viral activity against SARS-CoV-2.Promising docking outcomes have been executed which evidenced the worthy of these selected herbal remedies for future drug development to combat coronavirus disease.
基金supported by Science and Technology Innovation Fund of Guangdong Medical College(No.STIF 201107)
文摘Objective:To identify novel drug targets for treatment of Plasmodium falciparum.Methods: Local BT.ASTP were used to find the proteins non-homologous to human essential proteins as novel drug targets.Functional domains of novel drug targets were identified by InterPro and Pfam.3D structures of potential drug targets were predicated by the SWISS-MODEL workspace. Ligands and ligand-binding sites of the proteins were searched by Ef-seek.Results:Three essential proteins were identified that might be considered as potential drug targets.AAN37254.1 belonged to 1-deoxy-D-xylulose 5-phosphate reductoisomerase,CAD50499.1 belonged to chorismale synthase,CAD51220.1 belonged to FAD binging 3 family,but the function of CAD51220.1 was unknown.The 3D structures,ligands and ligand-binding sites of AAM37254.1 and CAD50499.1 were successfully predicated.Conclusions:Two of these potential drug targets are key enzymes in 2-C-methyl-d-erythritol 4-phosphate pathway and shikimate pathway, which are absent in humans,so these two essential proteins are good potential drug targets.The function and 3D structures of CAD50499.1 is still unknown,it still need further study.
文摘The drug searching for combating the present outbreak of Ebola virus infection is the urgent activity at present.Finding the new effective drug at present must base on the molecular analysis of the pathogenic virus.The in-depth analysis of the viral protein to find the binding site,active pocket is needed.Here,the authors analyzed the envelope glycoprotein GP2 from Ebola virus.Identification of active pocket and protein draggability within envelope glycoprotein GP2 from Ebola virus was done.According to this assessment,7 active pockets with varied draggability could be identified.
基金Supported by the Natural Science Foundation of Guangdong Province(No.2015A030311012)the Science and Technology Project of Guangzhou City(No.201607010215)
文摘Natural products are characterized with diverse structures and biological activities. They show a certain degree of adaptability to human beings. However, they need to be modified to increase their druggability. Several strategies including pharmacophore similarity, physicochemical property optimization, and bioactivity focus may help to make them more drug-like candidates.
文摘In the era of precision oncology,molecular profiling of tumor biopsy or plasma(also known as liquid biopsy)derived from patients with cancer is pivotal in guiding treatment selection.Liquid biopsy allows for the identification of druggable biomarkers,facilitating optimal cancer care management.1 Non-small cell lung cancer(NSCLC)is at the forefront because of the diverse genetic biomarkers currently approved for guiding targeted therapies.Mesenchymal epithelial transition(MET)is a receptor tyrosine kinase with pleiotropic functions,such as initiating and sustaining neoplastic transformation,driving cancer clonal evolution,and progression toward metastasis after treatment initiation and under therapeutic pressure.2 Exon 14 skipping(METex14skipping)and amplification(METamp)are two important MET dysregulations in NSCLC with distinct oncogenic roles.The concurrent presence of these two MET alterations in patients with NSCLC has rarely been reported,and knowledge of their collective impact on patient response to MET inhibitors such as capmatinib remains elusive.In this paper,we report the case of a 60-year-old woman diagnosed with lung adenocarcinoma and brain metastasis who progressed on first-line(1L)osimertinib treatment with new liver metastasis,along with the outcomes of subsequent testing and treatment management.
基金supported by the Guangdong Local Innovation Team Program(2019BT02Y262,China)National Natural Science Foundation of China(U20A20101,82274002,22175083)+2 种基金Key-Area Research and Development Program of Guangdong Province(2023B1111050008,China)National Key Research and Development Program of China(2022YFA1206900,2023YFA0914200)Science and Technology Innovation Project of Guangdong Medical Products Administration(S2021ZDZ042,2023ZDZ06,2024ZDZ08,China).
文摘Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)mice.Besides,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production.Due to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed cells.The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly.By encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,respectively.The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated biotransformation.In summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.
基金supported by the National Basic Research Program of China(973 Program,2010CB833200)National Natural Science Foundation of China(90713044,21032002)+1 种基金SHMCST (08431903000)the Fundamental Research Funds for the Central Universities(1082020502)
文摘Inhibitory effect on tumor necrosis factor-c~ （TNF-c0 production by sinomenine derivatives with embedment of small drug-like nitrogen hetereocyclic moieties has been studied in this work. Several new sinomenine derivatives having chlorophenyl sub- stituent have been found to exhibit much more potent TNF-a inhibitory activity than natural sinomenine and other derivatives.
基金the financial support from the CAMS Innovation Fund for Medical Sciences(2021-I2M-1-030,China)the Science and Technology Commission Foundation of Beijing(Z221100007922045,China).
文摘The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections.Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AzD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity.The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase(GyrB,IC_(50)=49 nmol/L)and a modest inhibitory effect on TopoⅣ(ParE,IC_(50)=1.513μmol/L)of Staphylococcus aureus.It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration(MIC)of less than 0.03μg/mL,which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S.aureus.Compound 28 had better protective effects than the positive control drugs such as DS-2969(5)and AZD5099(6)in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus(MRSA)infection.It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models.Moreover,compound 28 has much lower mitochondrial toxicity than AZD5099(6)as well as excellent therapeutic indexes and pharmacokinetic properties.At present,compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection.On the other hand,compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli(MIC=1μg/mL),which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently.In addition,the structure-activity relationships of the compounds were also studied.
