Transcription Factor DLX5 As a New Target for Promising Antitumor Agents

Timakhov, Roman A.; Федичев, П. О.; Vinnik, Andrei; Testa, Joseph R.; Фаворова, О. О.

doi:10.32607/20758251-2011-3-3-47-51

Cited by 3 publications

(1 citation statement)

References 19 publications

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“…To identify potential hits, we employed a virtual screening protocol. This protocol, performed using QUANTUM software, 32–34 included fast molecular docking for the generation of binding poses and molecular dynamics simulations to rank the ligand poses according to their binding affinities. The simulations were implemented using a proprietary version of the MM/Poisson Boltzman–Surface Area (MM/PB–SA) force field.…”

mentioning

confidence: 99%

Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein

Zentner

Sierra

Maciunas

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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Due to the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The HIV-1 matrix (MA) protein is an essential viral component with established roles in the assembly of the virus. Using virtual and surface plasmon resonance (SPR)-based screening, we describe the identification of the first small molecule to bind to the HIV-1 MA protein and to possess broad range anti-HIV properties.

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mentioning

confidence: 99%

Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein

Zentner

Sierra

Maciunas

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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Identification of a Small‐Molecule Inhibitor of HIV‐1 Assembly that Targets the Phosphatidylinositol (4,5)‐bisphosphate Binding Site of the HIV‐1 Matrix Protein

et al. 2013

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The development of drug resistance remains a critical problem for current HIV-1 antiviral therapies, creating a need for new inhibitors of HIV-1 replication. We previously reported on a novel anti-HIV-1 compound, N(2)-(phenoxyacetyl)-N-[4-(1-piperidinylcarbonyl)benzyl]glycinamide (14), that binds to the highly conserved phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P(2)) binding pocket of the HIV-1 matrix (MA) protein. In this study, we re-evaluate the hits from the virtual screen used to identify compound 14 and test them directly in an HIV-1 replication assay using primary human peripheral blood mononuclear cells. This study resulted in the identification of three new compounds with antiviral activity; 2-(4-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl})-1-piperazinyl)-N-(4-methylphenyl)acetamide (7), 3-(2-ethoxyphenyl)-5-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-1,2,4-oxadiazole (17), and N-[4-ethoxy-3-(1-piperidinylsulfonyl)phenyl]-2-(imidazo[2,1-b][1,3]thiazol-6-yl)acetamide (18), with compound 7 being the most potent of these hits. Mechanistic studies on 7 demonstrated that it directly interacts with and functions through HIV-1 MA. In accordance with our drug target, compound 7 competes with PI(4,5)P(2) for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4,5)P(2) binding site of MA decreased the antiviral effect of compound 7. Additionally, compound 7 displays a broadly neutralizing anti-HIV activity, with IC(50) values of 7.5-15.6 μM for the group M isolates tested. Taken together, these results point towards a novel chemical probe that can be used to more closely study the biological role of MA and could, through further optimization, lead to a new class of anti-HIV-1 therapeutics.

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Prediction of the Potential Efficacy of Dlx5 in Immunotherapy for Hypopharyngeal Cancer through Integrated Bulk and Single-Cell RNA Sequencing

yao,

Lianhe,

Jing

2024

Preprint

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Background: Immunotherapy, as a personalized treatment strategy, has displayed promising potential in the management of head and neck squamous cell carcinoma. Nevertheless, the heterogeneity and initial resistance of hypopharyngeal squamous cell carcinoma present new obstacles to treatment, highlighting the urgent need for identifying novel predictive biomarkers to develop more targeted and effective treatment approaches. Method: We employed the CIBERSORT algorithm, which quantifies immune cell composition, along with Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene modules associated with tumor immune infiltration of CD4+ T cells. We integrated single-cell sequencing technology to complement each other, conducting bidirectional screening to narrow down molecular associations with tumors. By constructing Protein-Protein Interaction (PPI) networks and conducting clinical Kaplan-Meier analysis, we identified crucial hub genes. We calculated tumor mutation rates, immune checkpoint expression, chemokine factors, and their corresponding receptor correlations to predict the efficacy of immunotherapy targeting DLX5. The R package "oncopredict" was utilized to compute drug sensitivity for each sample, inferring potential chemotherapeutic drugs targeting DLX5. Finally, we explored the precancerous phenotype of DLX5 in the Fadu cell line. Result: Bulk RNA sequencing and single-cell RNA sequencing revealed that in hypopharyngeal squamous cell carcinoma, the prognostically associated EGFR and DLX5 genes are upregulated. Immunological analysis showed a higher mutation rate of DLX5, which is significantly positively correlated with immune checkpoints and chemokine factors. Most importantly, three small molecule compounds (BI.2536_1086, MN.64_1854, Ulixertinib_2047) were identified, which could be potential drugs for treating hypopharyngeal cancer patients. Finally, high expression of DLX5 promoted proliferation, invasion, and migration of hypopharyngeal cancer cells. Conclusion： The association of Dlx5 with CD4+ T cells in hypopharyngeal cancer correlates with the immunological characteristics of the disease and the potential efficacy of immune checkpoint inhibitor therapy. These results indicate that DLX5 might respond well to immunotherapy, shedding light on the role of Dlx5 in hypopharyngeal cancer, providing crucial insights and offering vital information for the development of personalized immunotherapeutic strategies.

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Transcription Factor DLX5 As a New Target for Promising Antitumor Agents

Cited by 3 publications

References 19 publications

Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein

Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein

Identification of a Small‐Molecule Inhibitor of HIV‐1 Assembly that Targets the Phosphatidylinositol (4,5)‐bisphosphate Binding Site of the HIV‐1 Matrix Protein

Prediction of the Potential Efficacy of Dlx5 in Immunotherapy for Hypopharyngeal Cancer through Integrated Bulk and Single-Cell RNA Sequencing

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