Cancer Drug Targets Research Articles

Evaluation of Potential EGFR Inhibitors for Non-small Cell Lung Cancer: A Structure-based Virtual Screening and Molecular Dynamics Study

Non-small cell lung cancer is a leading cause of cancer deaths globally. EGFR is one of the attractive drug targets for non small cell lung cancer. It was first identified receptor tyrosine kinase receptor. It plays a critical role in the variety of biological activity apoptosis, cell cycle progression, differentiation, development, and transcription. Somatic mutation occurs in human EGFR. After that the normal function of EGFR was over expressed can leads to develop lung cancer. In this study we have identified three potential compounds using structure based virtual screening. Then thus compounds were evaluated ADME properties, all the compounds are under acceptable range with predicted ADME properties, then thus protein-ligand complex stability were carried out using Gromacs. The stability of the protein-ligand complex is stable throughout entire simulation, especially MET 769 is significant for stability of the complex. Furthermore, invitro cytotoxicity assay were performed for the best one compounds against non small cell lung cancer cell line.

Exploring the Impact of Chitosan-Based Nanoparticles in Cancer Targeted Drug Delivery: A Bibliometric Review.

Over the last two decades, there has been a considerable increase in the usage of chitosan nanoparticles (CSNPs) for drug delivery applications in cancer treatment. However, a comprehensive bibliometric analysis of this emerging field is lacking. The current analysis pre-sents a detailed bibliometric assessment of the research evolution and trends in CSNPs for can-cer targeted-drug delivery from 2000 to 2022. A total of 626 publications from the Web of Science Core Collection (WoSCC) database were evaluated using VOSviewer, Bibliometrix, and MS Excel. An in-depth exploration was carried out to find publication trends, the most productive authors, affiliations, countries, and journals as well as the highly cited publications within this particular research domain. Ick Chan Kwon was the most prominent author who made significant contributions to this field. China was the leading country in terms of research on CSNPs for cancer-targeted drug delivery, followed by India and Iran. Concerning the total number of publications, The International Journal of Biological Macromolecules excelled as the leading journal in this research area. Furthermore, the research trends and hotspots were also identified through the analysis of the most commonly used keywords by the authors. Our analysis highlights the growing research interest in CSNPs for cancer drug delivery, emphasiz-ing the need for further exploration to unlock their full potential.

Potential drug targets for ovarian cancer identified through Mendelian randomization and colocalization analysis

Potential drug targets for ovarian cancer identified through Mendelian randomization and colocalization analysis

Characterization of mitochondrial DNA mutations in colorectal cancer progression by in silico approach and use as potential biomarkers for diagnosis and prognosis

BackgroundMitochondrial DNA variants are significant contributors to cancer progression, as evidenced by numerous findings. This study focuses on characterizing mitochondrial DNA mutations in colorectal cancer progression and their potential as biomarkers.MethodologyNext generation sequencing technology was employed to analyze mitochondrial DNA variants in tumor and adjacent normal tissues from 25 patients with colon/rectal cancer. In silico prediction tools (SIFT, Polyphen2, Mutation Assessor, and SNP&GO) were utilized to assess the pathogenicity of these variants. Additionally, homology modeling of mutated protein structures was conducted, and molecular dynamic simulations were performed to assess the impact of mutation on protein function.ResultsEighteen variants were identified across most tumor tissue samples, located in genes from Complex I, IV, and V. Among the identified variants, the V302M and S461 mutations in the MT-ND5 gene and L137F and L220P mutations in the ATP6 gene were predicted to be deleterious, potentially affecting protein function. 3D structural analysis of both wild-type and mutant proteins of MT-ND5 revealed changes in flexibility for the V302M and S461G mutations. The MT-ATP6 mutations L135F and L220P disrupt the interactions with surrounding residues and affect the overall function of protein. Further changes in protein dynamics of the mutated proteins by molecular dynamic simulations also indicate the effects; the mutations have on protein function.ConclusionMT-ND5 and MT-ATP6 variants could serve as potential biomarkers and drug targets in colorectal cancer. This study underscores the significance of mitochondrial DNA variants in cancer progression.

Identification of key signaling pathways and novel computational drug target for oral cancer, metabolic disorders and periodontal disease

AimDue to conventional endocrinological methods, there is presently no shared work available, and no therapeutic options have been demonstrated in oral cancer (OC) and periodontal disease (PD), type 2 diabetes (T2D), and obese patients. The aim of this study is to determine the similar molecular pathways and potential therapeutic targets in PD, OC, T2D, and obesity that may be used to anticipate the progression of the disease. MethodsFour Gene Expression Omnibus (GEO) microarray datasets (GSE29221, GSE15773, GSE16134, and GSE13601) are used for finding differentially expressed genes (DEGs) for T2D, obese, and PD patients with OC in order to explore comparable pathways and therapeutic medications. Gene ontology (GO) and pathway analysis were used to investigate the functional annotations of the genes. The hub genes were then identified using protein-protein interaction (PPI) networks, and the most significant PPI components were evaluated using a clustering approach. ResultsThese three gene expression-based datasets yielded a total of seven common DEGs. According to the GO annotation, the majority of the DEGs were connected with the microtubule cytoskeleton structure involved in mitosis. The KEGG pathways revealed that the concordant DEGs are connected to the cell cycle and progesterone-mediated oocyte maturation. Based on topological analysis of the PPI network, major hub genes (CCNB1, BUB1, TTK, PLAT, and AHNAK) and notable modules were revealed. This work additionally identified the connection of TF genes and miRNAs with common DEGs, as well as TF activity. ConclusionPredictive drug analysis yielded concordant drug compounds involved with T2D, OC, PD, and obesity disorder, which might be beneficial for examining the diagnosis, treatment, and prognosis of metabolic disorders and Oral cancer.

Interleukin-1 Receptor-Associated Kinase 1 in Cancer Metastasis and Therapeutic Resistance: Mechanistic Insights and Translational Advances.

Interleukin-1 Receptor Associated Kinase 1 (IRAK1) is a serine/threonine kinase that plays a critical role as a signaling transducer of the activated Toll-like receptor (TLR)/Interleukin-1 receptor (IL-1R) signaling pathway in both immune cells and cancer cells. Upon hyperphosphorylation by IRAK4, IRAK1 forms a complex with TRAF6, which results in the eventual activation of the NF-κB and MAPK pathways. IRAK1 can translocate to the nucleus where it phosphorylates STAT3 transcription factor, leading to enhanced IL-10 gene expression. In immune cells, activated IRAK1 coordinates innate immunity against pathogens and mediates inflammatory responses. In cancer cells, IRAK1 is frequently activated, and the activation is linked to the progression and therapeutic resistance of various types of cancers. Consequently, IRAK1 is considered a promising cancer drug target and IRAK1 inhibitors have been developed and evaluated preclinically and clinically. This is a comprehensive review that summarizes the roles of IRAK1 in regulating metastasis-related signaling pathways of importance to cancer cell proliferation, cancer stem cells, and dissemination. This review also covers the significance of IRAK1 in mediating cancer resistance to therapy and the underlying molecular mechanisms, including the evasion of apoptosis and maintenance of an inflammatory tumor microenvironment. Finally, we provide timely updates on the development of IRAK1-targeted therapy for human cancers.

Crispr-mediated genome editing reveals a preponderance of non-oncogene addictions as targetable vulnerabilities in pleural mesothelioma

Pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. In particular, the frequent loss of tumor suppressors, a key oncogenic driver of the disease that is therapeutically intractable, has hampered the development of targeted cancer therapies. Here, we interrogate the PM genome using CRISPR-mediated gene editing to systematically uncover PM cell susceptibilities and provide an evidence-based rationale for targeted cancer drug discovery. This analysis has allowed us to identify with high confidence numerous known and novel gene dependencies that are surprisingly highly enriched for non-oncogenic pathways involved in response to various stress stimuli, in particular DNA damage and transcriptional dysregulation. By integrating genomic analysis with a series of in vitro and in vivo functional studies, we validate and prioritize several non-oncogene addictions conferred by CDK7, CHK1, HDAC3, RAD51, TPX2, and UBA1 as targetable vulnerabilities, revealing previously unappreciated aspects of PM biology. Our findings support the growing consensus that stress-responsive non-oncogenic signaling plays a key role in the initiation and progression of PM and provide a functional blueprint for the development of unprecedented targeted therapies to combat this formidable disease.

421 (PB409): XPR1, key regulator of phosphate homeostasis is a potential drug target for ovarian and lung cancer

421 (PB409): XPR1, key regulator of phosphate homeostasis is a potential drug target for ovarian and lung cancer

324 (PB312): Comprehensive Omics and Phenotypic Data Integration for Enhanced Drug Target and Biomarker Discovery in Cancer

324 (PB312): Comprehensive Omics and Phenotypic Data Integration for Enhanced Drug Target and Biomarker Discovery in Cancer

Exploring retinal degenerative diseases through CRISPR-based screening.

The CRISPR (Clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein9) system has emerged as a powerful genetic tool, gaining global recognition as a versatile and efficient gene-editing technique. Its transformation into a high-throughput research platform, CRISPR Screening, has demonstrated wide applicability across various fields such as cancer biology, virology, and drug target discovery, resulting in significant advances. However, its potential in studying retinal degenerative diseases remains largely unexplored, despite the urgent need for effective treatments arising from an incomplete understanding of disease mechanisms. This review aims to present a comprehensive overview of the evolution and current state of CRISPR tools and CRISPR screening methodologies. Noteworthy pioneering studies utilizing these technologies are discussed, alongside experimental design guidelines, including positive and negative selection strategies and delivery methods for sgRNAs (single guide RNAs) and Cas proteins. Furthermore, we explore existing in vitro models appropriate for CRISPR screening in retinal research and identify relevant research questions that could be addressed through this approach. It is anticipated that this review will stimulate innovation in retinal research, facilitating a deeper comprehension of retinal pathophysiology and paving the way for groundbreaking therapeutic interventions and enhanced patient outcomes in the management of retinal degenerative disorders.

The Inhibitory Effects of the Natural Stilbene Piceatannol on Lactate Transport In Vitro Mediated by Monocarboxylate Transporters.

Lactate, a signaling molecule and energy source, crosses membranes through monocarboxylate transporters (MCTs). MCT1 and MCT4 are potential cancer drug targets due to their role in metabolic reprogramming of cancer cells. Stilbenes, plant secondary metabolites found in several food sources, have anticancer effects, though their mechanisms of action are not well understood. This study links the anticancer activity of natural stilbenes to tumor cell lactate metabolism. The impact of resveratrol, pinostilbene, pterostilbene, rhapontigenin, and piceatannol on lactate transport is studied using a fluorescence resonance energy transfer (FRET)-based lactate sensor. The viability and migration of cells expressing MCT1 or MCT4 are also evaluated. Piceatannol inhibits MCT1 effectively at low micromolar concentrations, with less effect on MCT4. All stilbenes significantly reduce cell viability and migration. These findings indicate that both MCTs are stilbene targets, with piceatannol highlighted as a cost-effective, low-toxicity compound for studying MCTs in cancer, providing a new mechanism of action of the therapeutic and nutraceutical effects of natural polyphenols. This enriches the understanding of dietary polyphenols in cancer prevention and therapy.

Network pharmacology combined with molecular docking revealed the potential targets of Coridius chinensis in prostate cancer treatment.

Prostate cancer (PCa) has high morbidity and mortality rates in elderly men. With a history of thousands of years, traditional Chinese medicine derived from insects could be an important source for developing cancer-targeted drugs to prevent tumorigenesis, enhance therapeutic effects, and reduce the risk of recurrence and metastasis. Multiple studies have shown that Coridius chinensis (Cc) has anticancer effects. To elucidate the mechanism of action of Cc against PCa via network pharmacology and molecular docking. Potential targets for Cc and PCa were predicted using ChemDraw 19.0 software, the PharmMapper database and the GeneCards database. Then, the STRING database was used to construct the protein-protein interaction network. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and molecular docking analyses were subsequently conducted to identify the key targets, active ingredients and pathways involved. GO and KEGG analyses indicated that the PI3K-Akt signalling pathway was the critical pathway (P value < 1.0 × 10-8). Multiple targeting ingredients that can affect multiple pathways in PCa have been identified in Cc. Seven active compounds (asponguanosines A, asponguanine B, asponguanine C, aspongpyrazine A, N-acetyldopamine, aspongadenine B and aspongpyrazine B) were selected for molecular docking with 9 potential targets, and the results revealed that aspongpyrazine A and asponguanosine A are the main components by which Cc affects PCa (affinity<-5 kcal/mol, hydrogen bonding), but more studies are needed. We used network pharmacology to predict the bioactive components and important targets of Cc for the treatment of PCa, supporting the development of Cc as a natural anticancer agent.

Identifying new biomarkers and potential therapeutic targets for breast cancer through the integration of human plasma proteomics: a Mendelian randomization study and colocalization analysis.

The proteome is a crucial reservoir of targets for cancer treatment. While some targeted therapies have been developed, there are still significant challenges in early diagnosis and treatment, highlighting the need to identify new biomarkers and therapeutic targets for breast cancer. Therefore, we conducted a comprehensive proteome-wide Mendelian randomization (MR) study to identify novel biomarkers and potential therapeutic targets for breast cancer. Protein quantitative trait locus (pQTL) data were extracted from two published plasma proteome-wide association studies. Genetic variants associated with breast cancer were obtained from the Breast Cancer Association Consortium, which included 133,384 cases and 113,789 controls, and the Finnish cohort study, comprising 18,786 cases and 182,927 controls. We employed summary-based MR and colocalization methods to identify potential drug targets for breast cancer, which were subsequently validated using a two-sample MR approach. Finally, a protein-protein interaction (PPI) network was constructed to detect interactions between the identified proteins and existing cancer drug targets. Gene-predicted levels of ten proteins were associated with breast cancer risk. Decreased levels of CASP8, DDX58, CPNE1, ULK3, PARK7, and BTN2A1, as well as increased levels of TNFRSF9, TNXB, DNPH1, and TLR1, were linked to an elevated risk of breast cancer. Among these, CASP8 and DDX58 were supported by tier-one evidence, while CPNE1, ULK3, PARK7, and TNFRSF9 received tier-two evidence support. The remaining proteins, TNXB, BTN2A1, DNPH1, and TLR1, were supported by tier-three evidence. CASP8, DDX58, CPNE1, ULK3, PARK7, and TNFRSF9 have already been identified as targets in drug development and potential therapeutic targets for breast cancer treatment. Additionally, ULK3 showed promise as a prognostic biomarker for breast cancer. The present study identified several novel potential drug targets and biomarkers for breast cancer, providing new insights into its diagnosis and treatment. The integration of PPI and druggability evaluations enhances the prioritization of these therapeutic targets, paving the way for future drug development efforts.

Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure.

Domain Z7 of nuclear transcription factor ZNF711 has the consensus last metal-ligand H23 found in odd-numbered zinc fingers of this protein replaced by a phenylalanine. Ever since the discovery of ZNF711, it has been thought that Z7 is probably non-functional because of the H23F substitution. The presence of H26 three positions downstream prompted us to examine if this histidine could substitute as the last metal-ligand. The Z7 domain adopts a stable tertiary structure upon metal-binding. The NMR structure of Zn2+-bound Z7 shows the classical ββα-fold of CCHH zinc fingers. Mutagenesis and pH titration experiments indicate that H26 is not involved in metal binding and that Z7 has a tridentate metal-binding site comprised of only residues C3, C6, and H19. By contrast, an F23H mutation that introduces a histidine in the consensus position forms a tetradentate ligand. The structure of the WT Z7 is stable causing restricted ring-flipping of phenylalanines 10 and 23. Dynamics are increased with either the H26A or F23H substitutions and aromatic ring rotation is no longer hindered in the two mutants. The mutations have only small effects on the Kd values for Zn2+ and Co2+ and retain the high thermal stability of the WT domain above 80°C. Like two previously reported designed zinc fingers with the last ligand replaced by water, the WT Z7 domain is catalytically active, hydrolyzing 4-nitrophenyl acetate. We discuss the implications of naturally occurring tridentate zinc fingers for cancer mutations and drug targeting of notoriously undruggable transcription factors.

Essential cancer protein identification using graph-based random walk with restart

Protein-protein interaction (PPI) network analysis holds significant promise for cancer diagnosis and drug target identification. This paper introduces a novel random walk-based method called essential cancer protein identification using graph-based random walk with restart (EPI-GBRWR) to address this gap. This proposed method incorporates local and global topological features of proteins, enhancing the accuracy of essential protein identification in PPI networks. Starting with meticulous preprocessing of cancer gene datasets from NCBI, including breast, lung, colorectal, and ovarian cancers, and identifying a core set of common genes. The proposed method constructs PPI networks to capture complex protein interactions from these common cancer genes. Topological analysis, including a centrality measures matrix, is generated to perform the analysis to identify essential nodes. The study revealed that 40 essential proteins among breast, colorectal, lung and ovarian cancer showcase the potency of integrative methodologies in unravelling cancer complexity, signalling a transformative era in cancer research and treatment. The strength of the findings from the study has direct clinical relevance in cancer diseases. It contributes to the field of precision medicine to guide personalized treatment strategies.

Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade

Programmed cell death 1 (PD-1) is a premier cancer drug target for immune checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, cancer cell-intrinsic PD-1 functional regulation is not well understood. Here, we demonstrate induction of PD-1 in melanoma cells via type I interferon receptor (IFNAR) signaling and reversal of ICB efficacy through IFNAR pathway inhibition. Treatment of melanoma cells with IFN-α or IFN-β triggers IFNAR-mediated Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling, increases chromatin accessibility and resultant STAT1/2 and IFN regulatory factor 9 (IRF9) binding within a PD-1 gene enhancer, and leads to PD-1 induction. IFNAR1 or JAK/STAT inhibition suppresses melanoma-PD-1 expression and disrupts ICB efficacy in preclinical models. Our results uncover type I IFN-dependent regulation of cancer cell-PD-1 and provide mechanistic insight into the potential unintended ICB-neutralizing effects of widely used IFNAR1 and JAK inhibitors.

Multi-omics profiling combined with molecular docking reveals immune-inflammatory proteins as potential drug targets in colorectal cancer

Colorectal cancer is globally ranked as the third most common malignant tumor. Its development involves a complex biological process driven by various genetic and epigenetic alterations. To elucidate the biological significance of the extensive omics data, we conducted comparative multi-omics studies on colorectal cancer patients at different clinical stages. Bioinformatics methods were applied to analyze multi-omics datasets and explore the molecular landscape. Drug prediction and molecular docking also were conducted to assess potential therapeutic interventions. In vitro experiments were used to validate the inhibitory effect on the migration and proliferation of cell lines. The results indicate up-regulated proteins involved in immune-inflammatory related pathways, while biomarkers related to muscular contraction and cell adhesion are significantly down-regulated. Drug prediction, coupled with in vitro experiments, suggests that AZ-628 may act as a potential drug to inhibit the proliferation and migration of CRC cell lines HCT-116 and HT-29 by regulating the aforementioned key biological pathways or proteins. Complementing these findings, metabolomics analysis unveiled a down-regulation of key carbon metabolism pathways, alongside an up-regulation in amino acid metabolism, particularly proline metabolism. This metabolic shift may reflect an adaptive response in cancer cells, favoring specific amino acids to support their growth. Together, these integrated results provide valuable insights into the intricate landscape of tumor development, highlighting the crossroads of immune regulation, cellular structure, and metabolic reprogramming in the tumorigenic process and providing valuable insights into cancer pathology.

Synthesis and characterization of nickel-based MOFs: Enhancing photocatalysis and targeted cancer drug delivery

Metal–organic frameworks (MOFs) are intricate molecular solids formed by connecting organic ligands with metal or metal–cluster binding sites. They have exceptional characteristics such as expansive surface area, adaptability, and meticulously structured porosity, rendering them valuable in various applications including photocatalytic degradation and drug delivery systems. In this investigation, a benign Ni-based MOF was synthesized using benzene 1,4dicarboxylic acid as a linker and dimethyl sulfoxide as a solvent through the hydrothermal approach within a Teflon autoclave. The synthesized MOFs were precisely characterized using techniques such as X-ray diffraction, scanning electron microscope with energy-dispersive X-ray analysis, Fourier-transform infrared (FTIR) spectroscopy, thermogravimetric analysis, and N2-sorption measurements. The photocatalytic efficiency of the Ni-based MOF was explored against Congo red under visible light exposure, with the proposed mechanism involving electron transfer from photoexcited organic ligands to metallic clusters, resulting in a degradation efficiency of 98.68 % after 145 min. Furthermore, the Ni-based MOFs, when loaded with the anticancer drug cisplatin, displayed notable capabilities in drug delivery against the human breast cancer cell line MDA-MB-231, leading to a 35.26 % reduction in cell viability. Cytotoxicity assessments using the MTT assay revealed that the nano-carriers hindered cell proliferation with an IC50 value of 46.84 μg/mL.

Clinical value of guideline recommended molecular targets and genome targeted cancer therapies: cross sectional study

ObjectiveTo assess the clinical benefit and actionability of molecular targets for genome targeted cancer drugs recommended for clinical practice by the National Comprehensive Cancer Network (NCCN).DesignCross sectional study.Participants/settingGenome targeted cancer...

Unveiling the Protective Role of Metformin against Chemotherapyinduced Cardiotoxicity: A Comprehensive Scoping Review on Nonclinical Studies.

Chemotherapy therapies are effective in treating cancer, but they can have harmful effects on the cardiovascular system. This study explores the possible role of metformin in reducing the cardiac damage caused by chemotherapy. In this scoping review, we conducted a comprehensive literature search on electronic databases (PubMed, Scopus, and Web of Science (ISI)) until November 2023. The manuscript was screened regarding the role of metformin in chemotherapy-induced cardiotoxicity. Finally, 26 papers were selected after double screening. Chemotherapy has the potential to damage and cause cell death in the heart, resulting in molecular, biochemical, and histological changes compared to an untreated group. However, co-treatment with metformin may offer protection by preventing or reversing these harmful effects on cardiac cells. Metformin's cardioprotective properties are thought to be due to its ability to modulate oxidative stress, inflammation, autophagy, and the apoptotic pathway. The present study strongly suggests that metformin is an effective solution to chemotherapy-induced cardiotoxicity. Metformin can alleviate the harmful effects of chemotherapy on the heart by affecting oxidative stress, inflammation, autophagy, and apoptosis pathways. However, it is essential to note that the use of metformin may have some drawbacks, as it is a non-targeted therapy and could potentially reduce the effectiveness of targeted cancer drugs. Despite this, the potential benefits of using metformin in clinical settings cannot be ignored. Further studies are necessary to determine the specifics of this interaction. Still, the promising results of this review suggest that metformin may be an essential tool in the fight against chemotherapy-induced cardiotoxicity.