A New Renieramycin T Right-Half Analog as a Small Molecule Degrader of STAT3
<p>Derivatives of the RT right-half analogs—DH_17, DH_20, DH_23, DH_26, DH_28, DH_30, and DH_31. (<b>A</b>) The structure of Renieramycin T, TM-(−)-18, and the core structure of the RT right-half analog with R. R represents the position of the pyridyl, thiazolyl, or naphthalenyl group in ring C of the RT right-half analog, respectively. (<b>B</b>) Structures of the present RT right-half analogs: DH_17, DH_20, DH_23, DH_26, DH_28, DH_30, and DH_31. (<b>C</b>) Step-by-step synthesis for derivatives of RT right-half analogs.</p> "> Figure 2
<p>The effect of RT right-half analogs on cytotoxicity in NSCLC and human normal lung epithelial (BEAS-2B) cell lines and apoptotic cell death in NSCLC cells. (<b>A</b>) NSCLC H292 and H460 cells were treated with derivatives of RT right-half analogs for 24 h and analyzed using MTT assay to assess cytotoxicity. (<b>B</b>) IC<sub>50</sub> values for H292 and H460 cell lines were calculated. (<b>C</b>) BEAS-2B cells were treated with DH_28, DH_30, DH_31, and TM-(−)-18 for 24 h. The cytotoxic effects were evaluated using an MTT assay, and the IC<sub>50</sub> values for BEAS-2B cells were determined. (<b>D</b>) H292 and H460 cells were seeded and treated with 0–10 μM of DH_28, DH_30, and DH_31 for 24 h. Hoechst 33342 and PI were used to stain the cell nuclei. Images were obtained under a fluorescence microscope. (<b>E</b>) The percentages of cell death were calculated based on the stained images in H292 and H460 cells. Data represent the mean ± SD (<span class="html-italic">n</span> = 3). *, **, and *** indicate a statistically significant difference between the treated and the untreated cells at <span class="html-italic">p</span> < 0.05, <span class="html-italic">p</span> < 0.01, and <span class="html-italic">p</span> < 0.001, respectively.</p> "> Figure 3
<p>Putative analysis of NSCLC against DH_31 and the effect of DH_31 on EMT-association proteins. (<b>A</b>) Venn diagram of NSCLC and DH_31 targets and GO enrichment analysis of putative targets was performed to clarify the relevant biologic processes (<span class="html-italic">p</span> < 0.01). The y-axis represents GO terms, and the x-axis indicates the number of genes enriched in that term. The color from blue to red indicates the value of <span class="html-italic">p</span>. The adjust (FDR) is becoming smaller with greater credibility and importance. (<b>B</b>) The expression levels of ZO1, ZEB1, Slug, Snail, N-cadherin, and Vimentin were visualized by fluorescence microscopy. Scale bar, 20 µm. Bar graphs show the relative levels of ZO1, ZEB1, Slug, Snail, N-cadherin, and Vimentin. (<b>C</b>) The protein expression levels of ZO1, Slug, Snail, N-cadherin, Vimentin and β–actin were evaluated by Western blot analysis. The relative protein levels were calculated by densitometry. Data represent the mean ± SD (<span class="html-italic">n</span> = 3). *, **, and *** indicate a statistically significant difference between the treated and untreated cells at <span class="html-italic">p</span> < 0.05, <span class="html-italic">p</span> < 0.01, and <span class="html-italic">p</span> < 0.001, respectively.</p> "> Figure 4
<p>The effects of DH_31 on migration and anoikis resistance on NSCLC H460. (<b>A</b>) DH_31 decreased the migration of H460 cells. (<b>B</b>) The relative migration levels of the treated and untreated cells were determined at 24, 48, and 72 h. (<b>C</b>) DH_31 increased the sensitivity to anoikis in H460 cells. (<b>D</b>) The relative viability of cells was determined after culture under detachment conditions for 6, 12, and 24 h. Scale bar, 20 µm. Data represent the mean ± SD (<span class="html-italic">n</span> = 3). ** and *** indicate a statistically significant difference between the treated and the untreated cells at <span class="html-italic">p</span> < 0.01 and <span class="html-italic">p</span> < 0.001, respectively.</p> "> Figure 5
<p>STAT3 identified as a potential target of DH_31. (<b>A</b>) The top 10 targets among the 64 targets were ranked based on the number of degrees, visualized by the CytoHubba plugin. The degree values of the top 10 targets in the PPI network were ranked, with STAT3 having the highest degree. The intensity of the colors corresponded to the degree values, with purple indicating large values, pink indicating moderate values, and yellow indicating small values. (<b>B</b>) H460 cells treated with DH_31 (0–2.5 μM) for 24 h were stained with anti-STAT3 antibody (red) and examined using confocal laser scanning microscopy. Cell nuclei were stained with Hoechst 33342 (blue). Scale bar, 10 µm. Arrows denote localized STAT3 proteins. (<b>C</b>) The relative levels of STAT3 of H460 were determined by immunofluorescence analysis. (<b>D</b>) The protein expression levels of STAT3 and β–actin was evaluated by Western blot analysis. (<b>E</b>) The relative protein levels were calculated by densitometry. Data represent the mean ± SD (<span class="html-italic">n</span> = 3). * and *** indicate a statistically significant difference between the treated and untreated cells at <span class="html-italic">p</span> < 0.05 and <span class="html-italic">p</span> < 0.001, respectively.</p> "> Figure 6
<p>The effect of DH_31 on enhanced ubiquitin-mediated STAT3 proteasomal degradation in NSCLC H460. H460 cells were treated with DH_31 (0–2.5 μM) for 8 h. (<b>A</b>) The expression levels of STAT3 mRNA were determined by Real-time qPCR. (<b>B</b>) The ubiquitin–proteasome inhibitor MG132 reversed the inhibitory effect of DH_31 on the expression of the STAT3 protein. After treatment with or without MG132 (10 µM) for 1 h, cells were treated with DH_31 (0–2.5 µM) for 6 h. The STAT3 levels were measured using Western blot analysis and calculated by densitometry. (<b>C</b>) DH_31 induced the ubiquitin–proteasomal degradation of STAT3. After treatment with or without MG132 (10 µM) for 1 h, cells were treated with DH_31 (0 and 2.5 µM) for 6 h. The protein lysates were collected subsequent to STAT3 immunoprecipitation, and the ubiquitinated protein levels were measure by Western blot analysis. Ub-STAT3 levels were calculated by densitometry. Data represent the mean ± SD (<span class="html-italic">n</span> = 3). *, and ** indicate a statistically significant difference between the treated and untreated cells at <span class="html-italic">p</span> < 0.05 and <span class="html-italic">p</span> < 0.01, respectively. # and ## indicate a statistically significant difference from the cells without MG132 at <span class="html-italic">p</span> < 0.05 and <span class="html-italic">p</span> < 0.01, respectively.</p> "> Figure 7
<p>Domain structure of STAT3 and structure of DH_31 with in silico predicted binding configurations. (<b>A</b>) Schematic of the domain structure of STAT3 and the structure of the dimer interface of STAT3 (PDB: 1BG1) illustrating the surface locations of the DNA-binding domain (residues 321–494) (red) and the SH2 domain (residues 584–688) (green), (<b>B</b>) the binding interaction of DH_31 to the SH2 domain of STAT3, (<b>C</b>) the binding interaction of DH_31 to the DNA-binding domain, and (<b>D</b>) the binding interaction of TM-(−)-18 to the DNA-binding domain of STAT3. (<b>E</b>) The binding energy of DH_31 and TM-(−)-18 at the SH2 domain and the DNA-binding domain.</p> "> Figure 8
<p>The effect of DH_31 on the mRNA expression of EMT markers in NSCLC H460. (<b>A</b>) Schematic representation of the of STAT3 transcription factor binding sites in target genes. (<b>B</b>) The mRNA expression of <span class="html-italic">ZO1</span>, <span class="html-italic">Slug</span>, <span class="html-italic">Snail</span>, <span class="html-italic">N-cadherin</span>, and <span class="html-italic">Vimentin</span> in H460 cells treated with DH_31 (0–2.5 µM).</p> "> Scheme 1
<p>Synthesis of <b>2e</b>.</p> "> Scheme 2
<p>Synthesis of <b>2f</b>: DH_30.</p> "> Scheme 3
<p>Synthesis of <b>3a</b>: DH_17.</p> "> Scheme 4
<p>Synthesis of <b>3b</b>: DH_20.</p> "> Scheme 5
<p>Synthesis of <b>3c</b>: DH_23.</p> "> Scheme 6
<p>Synthesis of <b>3d</b>: DH_26.</p> "> Scheme 7
<p>Synthesis of <b>3e</b>: DH_28.</p> "> Scheme 8
<p>Synthesis of <b>3f</b>: DH_31.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Synthesis of Seven Derivatives of RT Right-Half Analog
2.2. Derivatives of RT Right-Half Analog Induce Cytotoxicity and Apoptosis
2.3. DH_31 Suppresses Metastasis Mechanism
2.4. DH_31 Inhibits Migration and Increases Sensitivity to Anoikis
2.5. DH_31 Decreases STAT3 Protein Expression
2.6. DH_31 Decreases STAT3 through the Induction of STAT3 Proteasomal Degradation
2.7. DH_31 Interactions with STAT3 Protein
2.8. DH_31 Suppresses mRNA Expression of EMT Markers
3. Discussion
4. Materials and Methods
4.1. Synthesis of Derivatives of RT Right-Half Analogs
Procedures for Synthesis of 2a–3f
4.2. Preparation of Stock Solution
4.3. Cell Lines and Reagents
4.4. Cell Viability Assay
4.5. Wound Healing Assay
4.6. Measurement of Cell Resistance to Anoikis
4.7. Database Mining of DH_31 Targets, and NSCLC-Associated Genes
4.8. Immunofluorescence Staining and Confocal Microscopy
4.9. Western Blot Assay
4.10. Immunoprecipitation Assay
4.11. Computational Molecular Docking
4.12. Quantitative Real-Time PCR
4.13. Statistics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Phookphan, P.; Racha, S.; Yokoya, M.; Ei, Z.Z.; Hotta, D.; Zou, H.; Chanvorachote, P. A New Renieramycin T Right-Half Analog as a Small Molecule Degrader of STAT3. Mar. Drugs 2024, 22, 370. https://doi.org/10.3390/md22080370
Phookphan P, Racha S, Yokoya M, Ei ZZ, Hotta D, Zou H, Chanvorachote P. A New Renieramycin T Right-Half Analog as a Small Molecule Degrader of STAT3. Marine Drugs. 2024; 22(8):370. https://doi.org/10.3390/md22080370
Chicago/Turabian StylePhookphan, Preeyaphan, Satapat Racha, Masashi Yokoya, Zin Zin Ei, Daiki Hotta, Hongbin Zou, and Pithi Chanvorachote. 2024. "A New Renieramycin T Right-Half Analog as a Small Molecule Degrader of STAT3" Marine Drugs 22, no. 8: 370. https://doi.org/10.3390/md22080370