Integrated bioinformatics analysis of potential biomarkers and candidate drugs of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma(ESCC),the major subtype of esophageal carcinoma(ESCA),is one of the most lethal malignancies worldwide.This study aimed to identify potential biomarkers and/or therapeutic targets for ESCC.The datasets GSE44021,GSE77861,GSE20347,and GSE29001 retrieved from the Gene Expression Omnibus(GEO)database contained 117 ESCC tissues and 109 normal tissues.Differentially expressed genes(DEGs)associated with ESCC were identified using the GEO2R tool.Dysregulated pathways associated with ESCC mainly included mitotic regulation,cell cycle,ECM-receptor interaction,DNA replication,etc.The protein-protein interaction(PPI)network of overlapping DEGs was constructed and nine key genes(KGs)were identified from the complex interaction network using Degree,maximum neighborhood component(MNC),and maximal clique centrality(MCC)algorithms.Expression patterns of KGs at the transcriptional and translational levels were validated using ESCC-related data from the Cancer Genome Atlas(TCGA),Oncomine,and Human Protein Atlas(HPA)databases.Genetic alterations calculation,immune cell infiltrates evaluation,methylation analysis,prognostic analysis,transcription factors(TFs)and miRNAs regulatory networks construction,and targeted drug prediction were further performed.It was also found that the knockout of these KGs affected the survival of more than two types of ESCC cells by genome-wide CRISPR-Cas9 dropout screens.In conclusion,we identified KGs,TFs,and miRNAs with biomarker potential(e.g.,NDC80,BUB1,TOP2A,AURKA,AURKB,TTK,UBE2C,TPX2,BUB1B,E2F1,and hsa-miR-483-5p)and 23 candidate targeted drugs for ESCC by utilizing an integrated multi-omics approach.These findings provide additional insights into uncovering the molecular mechanism and improving the efficiency of clinical diagnosis and treatment for ESCC.

Advances on biological evaluation methods of programmed cell death protein-1/ligand-1 inhibitors

Immuno-oncology represents a groundbreaking and well-established field within cancer treatment.Among the various immuno-oncology targets,the exploration of programmed cell death-1/ligand-1 for drug discovery has proven to be one of the most successful endeavors.Remarkably,it took nearly 30 years from the initial target identification to the clinical approval of monoclonal antibodies.Providing suitable and reliable bioassays for drug candidate evaluation is of paramount importance throughout the early stages of drug discovery,from lead compound identification to in vivo efficacy testing.This assay review aims to shed light on diverse assays reported in the literature for testing antagonism activity and efficacy of programmed cell death-1/ligand-1 inhibitors.Each of these assays possesses inherent advantages and can be applied in different research scenarios.The insights presented in this summary can serve as a valuable resource for scientists in this field,aiding in the selection of appropriate assays for their specific investigations.

Design and optimization of piperidinesubstituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles

HIV-1 reverse transcriptase(RT)has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome(AIDS),but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors(NNRTIs).This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drugresistance profiles,reduced toxicity,and excellent druggability.A series of diarylpyrimidine(DAPY)derivatives were prepared via structural modifications of the leads K-5a2 and 25a.Among them,15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel,being 1.6-fold(WT,EC_(50) Z 1.75 nmol/L),3.0-fold(L100I,EC_(50) Z 2.84 nmol/L),2.4-fold(K103N,EC_(50) Z 1.27 nmol/L),3.3-fold(Y181C,EC50 Z 5.38 nmol/L),2.9-fold(Y188L,EC_(50) Z 7.96 nmol/L),2.5-fold(E138K,EC_(50) Z 4.28 nmol/L),4.8-fold(F227L/V106A,EC_(50) Z 3.76 nmol/L)and 5.3-fold(RES056,EC_(50) Z 15.8 nmol/L)more effective than that of the marketed drug ETR.Molecular docking results illustrated the detailed interactions formed by compound 15a and WT,F227L/V106A,and RES056 RT.Moreover,15a-HCl carried outstanding pharmacokinetic(t1/2 Z 1.32 h,F Z 40.8%)and safety profiles(LD_(50)>2000 mg/kg),which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.

Spatiotemporally resolved metabolomics and isotope tracing reveal CNS drug targets

Deconvolution of potential drug targets of the central nervous system(CNS)is particularly challenging because of the complicated structure and function of the brain.Here,a spatiotemporally resolved metabolomics and isotope tracing strategy was proposed and demonstrated to be powerful for deconvoluting and localizing potential targets of CNS drugs by using ambient mass spectrometry imaging.This strategy can map various substances including exogenous drugs,isotopically labeled metabolites,and various types of endogenous metabolites in the brain tissue sections to illustrate their microregional distribution pattern in the brain and locate drug action-related metabolic nodes and pathways.The strategy revealed that the sedative-hypnotic drug candidate YZG-331 was prominently distributed in the pineal gland and entered the thalamus and hypothalamus in relatively small amounts,and can increase glutamate decarboxylase activity to elevateγ-aminobutyric acid(GABA)levels in the hypothalamus,agonize organic cation transporter 3 to release extracellular histamine into peripheral circulation.These findings emphasize the promising capability of spatiotemporally resolved metabolomics and isotope tracing to help elucidate the multiple targets and the mechanisms of action of CNS drugs.

Identification of Key Genes as Potential Drug Targets for Gastric Cancer

Gastric cancer(GC)is one of the most common cancers and ranks the third in cancer mortality all over the world.The goal of this study was to identify potential hub-genes,highlighting their functions,signaling pathways,and candidate drugs for the treatment of GC patients.We used publicly available next generation sequencing(NGS)data to identify differentially expressed(DE)genes.The top DE genes were mapped to STRING database to construct the protein-protein interaction(PPI)network and top hub genes were selected for further analysis.We found a total of 1555 DE genes with 870 upregulated and 685 downregulated genes in GC.We selected the top 400(200 upregulated and 200 downregulated)genes to construct a PPI network and extracted the top 15 hub genes.The gene ontology(GO)term and kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analyses of the 15 hub genes exposed some important functions and signaling pathways that were significantly associated with GC patients.The survival analysis of the hub genes disclosed that the lower expressions of the three hub genes CDH2,COL4A1,and COL5A2 were associated with better survival of GC patients.These three genes might be the candidate biomarkers for the diagnosis and treatment of GC.Then,we considered 3 key proteins(genomic biomarkers)(COL4A1,CDH2,and CO5A2)as the drug target proteins(receptors),performed their docking analysis with the 102 meta-drug agents,and found Everolimus,Docetaxel,Lanreotide,Venetoclax,Temsirolimus,and Nilotinib as the top ranked 6 candidate drugs with respect to our proposed target proteins for the treatment against GC patients.Therefore,the proposed drugs might play vital role for the treatment against GC patients.

Jun12682,a potent SARS-CoV-2 papain-like protease inhibitor with exceptional antiviral efficacy in mice

Recently,a collaborative research study published in Science,led by Jun Wang,Xufang Deng,Eddy Arnold,and Francesc Xavier Ruiz1,identified a series of potent small molecule inhibitors that specifically target SARS-CoV-2 papain-like protease(PL^(pro)).The study demonstrated nanomolar PL^(pro) inhibitory potency with K_(i) values ranging from 13.2 to 88.2 nmol/L.By employing a structure-based drug design strategy,the researchers discovered an exceptionally promising compound,named Jun12682,that effectively targets both the newly discovered ubiquitin Val70(Val70^(Ub))-binding site and the known blocking loop(BL2)groove near the S4 subsite of PL^(pro).Furthermore,studies on the mechanism of action revealed that Jun12682 inhibits the deubiquitinating and deISGylating activities of PLpro,which are crucial for antagonizing the host’s innate immune response upon viral infection.Structural biology studies confirmed the“two-pronged”binding mode of Jun12682,aligning perfectly with their drug design rationale.Importantly,Jun12682 exhibited potent antiviral activity against SARS-CoV-2 and its variants,including nirmatrelvir-resistant mutants,in Caco-2 cells(EC_(50):0.44-2.02 μmol/L).It is noteworthy that its oral administration significantly improved survival rates and alleviated both lung virus loads and histopathological lesions in a lethal SARS-CoV-2 mouse model.In conclusion。

Research and development of Chinese anti-COVID-19 drugs

The outbreak and spread of coronavirus disease 2019(COVID-19)highlighted the importance and urgency of the research and development of therapeutic drugs.Very early into the COVID-19 pandemic,China has begun developing drugs,with some notable progress.Herein,we summarizes the anti-COVID-19 drugs and promising drug candidates originally developed and researched in China.Furthermore,we discussed the developmental prospects,mechanisms of action,and advantages and disadvantages of the anti-COVID-19 drugs in development,with the aim to contribute to the rational use of drugs in COVID-19 treatment and more effective development of new drugs against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and the variants.Neutralizing antibody is an effective approach to overcome COVID-19.However,drug resistance induced by rapid virus mutation will likely to challenge neutralizing antibodies.Taking into account current epidemic trends,small molecule drugs have a crucial role in fighting COVID-19 due to their significant advantage of convenient administration and affordable and broad-spectrum.Traditional Chinese medicines,including natural products and traditional Chinese medicine prescriptions,contribute to the treatment of COVID-19 due to their unique mechanism of action.Currently,the research and development of Chinese anti-COVID-19 drugs have led to some promising achievements,thus prompting us to expect even more rapidly available solutions.

Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

The phosphatidylinositol 3-kinase(PI3K) pathway is frequently activated in human cancers.Class I PI3 Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate(PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate(PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin(m TOR) to play key roles in carcinogenesis. Therefore, PI3 K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3 K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3 K inhibitor for cancer therapy. Dozens of other PI3 K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3 K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers,etc. This review provides an introduction to PI3 K and summarizes key advances in the development of PI3 K inhibitors.