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PloS One 2024Human sirtuin-2 (SIRT2) has emerged as an attractive drug target for a variety of diseases. The enzyme is a deacylase that can remove chemically different acyl...
Human sirtuin-2 (SIRT2) has emerged as an attractive drug target for a variety of diseases. The enzyme is a deacylase that can remove chemically different acyl modifications from protein lysine residues. Here, we developed a high-throughput screen based on a homogeneous time-resolved fluorescence (HTRF) binding assay to identify inhibitors of SIRT2's demyristoylase activity, which is uncommon among many ligands that only affect its deacetylase activity. From a test screen of 9600 compounds, we identified a small molecule that inhibited SIRT2's deacetylase activity (IC50 = 7 μM) as well as its demyristoylase activity (IC50 = 37 μM). The inhibitor was composed of two small fragments that independently inhibited SIRT2: a halogenated phenol fragment inhibited its deacetylase activity, and a tricyclic thiazolobenzimidazole fragment inhibited its demyristoylase activity. The high-throughput screen also detected multiple deacetylase-specific SIRT2 inhibitors.
Topics: Sirtuin 2; Humans; High-Throughput Screening Assays; Histone Deacetylase Inhibitors; Enzyme Inhibitors; Fluorescence
PubMed: 38913635
DOI: 10.1371/journal.pone.0305000 -
Heliyon Jun 2024Simultaneous inhibition of soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) with a single small molecule represents a novel therapeutic approach in...
Quinolinyl-based multitarget-directed ligands with soluble epoxide hydrolase and fatty acid amide hydrolase inhibitory activities: Synthetic studies and pharmacological evaluations.
Simultaneous inhibition of soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) with a single small molecule represents a novel therapeutic approach in treating inflammatory pain, since both targets are involved in pain and inflammation processes. In this study using multi-target directed ligands methodology we designed and synthesized 7 quinolinyl-based dual sEH/FAAH inhibitors, using an optimized microwave-assisted Suzuki-Miyaura coupling reaction and tested their potency in human FAAH and human, rat, and mouse sEH inhibition assays. The structure-activity relationship study showed that quinolinyl moiety is well tolerated in the active sites of both enzymes, yielding several very potent dual sEH/FAAH inhibitors with the IC values in the low nanomolar range. The most potent dual inhibitor was further evaluated in stability assay in human and rat plasma where it performed better than the standard Warfarin while study revealed that 1 mg/kg can inhibit acute inflammatory pain in male rats to a similar degree as the traditional nonsteroidal anti-inflammatory drug ketoprofen (30 mg/kg) after intraperitoneal injection. ADMET prediction studies for this dual inhibitor show favorable pharmacokinetic properties which will guide the future evaluations.
PubMed: 38912512
DOI: 10.1016/j.heliyon.2024.e32262 -
Frontiers in Chemistry 2024DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been...
DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids () to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060 μg/mL against , , and . had a MIC value of 0.050 μg/mL against , which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives , , , and against DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on DNA gyrase, with IC values ranging from 92 to 112 nM. These results indicate that , , , and are more effective than the reference novobiocin, which had an IC value of 170 nM. Compounds , , , and were subjected to additional assessment against topoisomerase IV. Compounds and , which have the highest efficacy in inhibiting gyrase, also demonstrated promising effects on topoisomerase IV. Compounds and exhibit IC values of 3.50 µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC value of 11 µM. Docking studies demonstrate the potential of compound as an effective dual inhibitor against DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.
PubMed: 38911996
DOI: 10.3389/fchem.2024.1419242 -
ACS Bio & Med Chem Au Jun 2024Synthetic modification of oligodeoxynucleotides (ODNs) via conjugation to nucleic acid binding small molecules can improve hybridization and pharmacokinetic properties....
Synthetic modification of oligodeoxynucleotides (ODNs) via conjugation to nucleic acid binding small molecules can improve hybridization and pharmacokinetic properties. In the present study, five Hoechst 33258 derived benzimidazoles were conjugated to T rich ODNs and their hybridization effectiveness was tested. Thermal denaturation studies revealed significant stabilization of complementary duplexes by ODN-benzimidazole conjugates, with the extent of stabilization being highly dependent on the length of the linker between DNA and benzimidazole. The increases in thermal stability were determined to be due to the binding of the benzimidazole moiety to the duplex. Circular dichroism and molecular modeling studies provided insights toward the influence of conjugation on duplex structure and how linker length impacts placement of the benzimidazole moiety in the minor groove. Furthermore, thermal denaturation studies with the complementary strand containing a single base mismatch or being RNA revealed that covalent conjugation of benzimidazoles to an ODN also enhances the sequence specificity. The fundamental studies reported herein provide a strategy to improve the stability and specificity properties of the ODN probes, which can be of use for targeting and diagnostics applications.
PubMed: 38911908
DOI: 10.1021/acsbiomedchemau.3c00074 -
Frontiers in Immunology 2024Immune checkpoint blockades (ICBs) have revolutionized cancer therapy through unleashing anti-tumor adaptive immunity. Despite that, they are usually effective only in a... (Review)
Review
Immune checkpoint blockades (ICBs) have revolutionized cancer therapy through unleashing anti-tumor adaptive immunity. Despite that, they are usually effective only in a small subset of patients and relapse can occur in patients who initially respond to the treatment. Recent breakthroughs in this field have identified innate immune checkpoints harnessed by cancer cells to escape immunosurveillance from innate immunity. MHC1 appears to be such a molecule expressed on cancer cells which can transmit a negative signal to innate immune cells through interaction with leukocyte immunoglobulin like receptor B1 (LILRB1). The review aims to summarize the current understanding of MHC1/LILRB1 axis on mediating cancer immune evasion with an emphasis on the therapeutic potential to block this axis for cancer therapy. Nevertheless, one should note that this field is still in its infancy and more studies are warranted to further verify the effectiveness and safety in clinical as well as the potential to combine with existing immune checkpoints.
Topics: Humans; Leukocyte Immunoglobulin-like Receptor B1; Neoplasms; Immunity, Innate; Animals; Immune Checkpoint Inhibitors; Tumor Escape; Histocompatibility Antigens Class I; Immunotherapy; Signal Transduction; Antigens, CD
PubMed: 38911856
DOI: 10.3389/fimmu.2024.1421092 -
ACS Omega Jun 2024Pathogen infection represents the greatest challenge to agricultural crop production, resulting in significant economic loss. Conventional pesticides are used to control...
Pathogen infection represents the greatest challenge to agricultural crop production, resulting in significant economic loss. Conventional pesticides are used to control such infection but can result in antimicrobial resistance and detrimental effects on the plant, environment, and human health. Due to nitric oxide's (NO) endogenous roles in plant immune responses, treatment with exogenous NO represents an attractive nonpesticide approach for eradicating plant pathogens. In this work, the antimicrobial activity of small-molecule NO donors of varying NO-release kinetics was evaluated against and , two prevalent plant pathogens. Intermediate NO-release kinetics proved to be most effective at eradicating these pathogens in vitro. A selected NO donor (methyl tris diazeniumdiolate; MD3) was capable of treating both bacterial infection of plant leaves and fungal infection of tomato fruit without exerting toxicity to earthworms. Taken together, these results demonstrate the potential for utilizing NO as a broad-spectrum, environmentally safe pesticide and may guide development of other NO donors for such application.
PubMed: 38911785
DOI: 10.1021/acsomega.4c01454 -
Annals of Translational Medicine Jun 2024The development of trastuzumab is among the most significant cancer drug development projects in the 20th century. Trastuzumab became a gamechanger for the treatment of... (Review)
Review
The development of trastuzumab is among the most significant cancer drug development projects in the 20th century. Trastuzumab became a gamechanger for the treatment of human epidermal growth receptor 2 (HER2) positive breast cancer, with a significant positive impact on disease recurrence and survival. The development of trastuzumab was the beginning of a new era of cancer drug development, which showed us the importance of understanding the molecular pathophysiology and drug mechanism of action. The drug-diagnostic codevelopment model, in which the drug is developed in parallel with a predictive biomarker assay, has had a significant impact on today's cancer drug development, and we are indebted to trastuzumab when it comes to the clinical enrichment trial design. Trastuzumab is not the only drug developed to target the HER2 protein. Over the past few decades, several new HER2 targeted therapies have been developed, including small-molecule tyrosine kinase inhibitors (TKI), monoclonal antibodies, and antibody-drug conjugates (ADC). In particular, the ADC trastuzumab deruxtecan seems to pave new avenues when it comes to HER2 targeted treatment not only for breast cancer, but also for gastric cancer and non-small cell lung cancer. With the development of trastuzumab as a reference point, this article will provide a brief summary of the efficacy of HER2 targeted therapy, including testing for HER2 positivity, as it has evolved over the past 25 years.
PubMed: 38911570
DOI: 10.21037/atm-23-153 -
Clinical Medicine Insights. Oncology 2024Antibody-drug conjugates (ADCs), combining the cytotoxicity of the drug payload with the specificity of monoclonal antibodies, are one of the rapidly evolving classes of... (Review)
Review
Antibody-drug conjugates (ADCs), combining the cytotoxicity of the drug payload with the specificity of monoclonal antibodies, are one of the rapidly evolving classes of anti-cancer agents. These agents have been successfully incorporated into the treatment paradigm of many malignancies, including non-small cell lung cancer (NSCLC). The NSCLC is the most prevalent subtype of lung cancer, having a considerable burden on the cancer-related mortality and morbidity rates globally. Several ADC molecules are currently approved by the Food and Drug Administration (FDA) to be used in patients with NSCLC. However, the successful management of NSCLC patients using these agents was met with several challenges, including the development of resistance and toxicities. These shortcomings resulted in the exploration of novel therapeutic targets that can be targeted by the ADCs. This review aims to explore the recently identified ADC targets along with their oncologic mechanisms. The ADC molecules targeting these biomarkers are further discussed along with the evidence from clinical trials.
PubMed: 38911453
DOI: 10.1177/11795549241260534 -
Journal of Cancer 2024T-box transcription factor 3 (TBX3) has been implicated in various malignant tumors, while its exact involvement in osteosarcoma (OS) remains unknown. Utilizing...
T-box transcription factor 3 (TBX3) has been implicated in various malignant tumors, while its exact involvement in osteosarcoma (OS) remains unknown. Utilizing microarray data and bulk and single-cell RNA-seq data and qRT-PCR, we compared TBX3 mRNA expression levels in different stages of OS. Diagnostic ability testing and prognosis analysis were conducted to better understand the clinical importance of TBX3. Enrichment analysis was performed using gene groups with biological functions similar to TBX3 in different stages of OS to investigate the potential role of TBX3 in OS progression. In addition, we predicted medications targeted at TBX3 and identified downstream target genes to gain a comprehensive understanding of its therapeutic direction and regulatory mechanism. TBX3 expression was highly upregulated in OS and was predominantly expressed in osteoblastic OS cells, with higher expression levels in metastatic tissues. TBX3 expression appeared somewhat suitable for discriminating between OS and normal samples, as well as different stages of OS. We found that TBX3 increased the malignant development of OS by altering cell cycle and cell adhesion molecules; exisulind and tacrolimus, which are targeted small-molecule medicines, were anticipated to counteract this dysregulation. The expression of CCNA2 could potentially be regulated by TBX3, contributing to OS advancement. TBX3 emerges as a potential biomarker for OS. In-depth research into its underlying molecular processes may offer new perspectives on treating OS.
PubMed: 38911382
DOI: 10.7150/jca.96168 -
Journal of Cancer 2024In this study, we aimed to elucidate the role of mitochondrial calcium uptake 1/2 (MiCU1/2) in breast cancer (BRCA) by employing a comprehensive multi-omics approach....
In this study, we aimed to elucidate the role of mitochondrial calcium uptake 1/2 (MiCU1/2) in breast cancer (BRCA) by employing a comprehensive multi-omics approach. Unlike previous research, we utilized a novel web application tailored for whole tumor tissue, single-cell, and spatial transcriptomics analysis to investigate the association between MiCU1/2 and the tumor immune microenvironment (TIME). Our gene set enrichment analysis (GSEA) provided insights into the primary biological effects of MiCU1/2, while our CRISPR-based drug screening repository identified potential effective drugs. Our study revealed that high MiCU1/2 expression serves as an independent diagnostic biomarker, correlating with advanced clinical status and indicating poorer recurrence-free survival (RFS) rates in BRCA patients. Additionally, spatial transcriptome analysis highlighted the heightened expression of MiCU1/2 in tumors and its relevance in surrounding immune cells. Furthermore, using the CIBERSORT algorithm, we discovered a positive correlation between MiCU1/2 levels and macrophage infiltration, underscoring their potential impact on immune infiltration. We also identified expression patterns of immune-related genes associated with responses against various immune cell types, including CXCL, MIF, GDF, SPP1, and IL16. Finally, our pharmacogenomic screening identified potential small molecule drugs capable of effectively targeting breast cancer cells with elevated MiCU1/2 expression. Overall, our study establishes MiCU1/2 as a promising novel biomarker for BRCA diagnosis and prognostic prediction, as well as a potential therapeutic target, highlighting the importance of exploring these pathways to advance patient care and outcomes in BRCA treatment.
PubMed: 38911376
DOI: 10.7150/jca.95979