The novel STAT3 inhibitor WZ-2-033 causes regression of human triple-negative breast cancer and gastric cancer xenografts

Zhong, Yan; Deng, Lin; Shi, Shuo; Huang, Qiuyao; Ouyang, Shumin; Mo, Jianshan; Zhu, Kai; Qu, Xinming; Liu, Peiqing; Wang, Yuanxiang; Zhang, Xiaolei

doi:10.1038/s41401-021-00718-0

Cited by 18 publications

(7 citation statements)

References 50 publications

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“…It has been demonstrated that the novel oral active molecular gel WBC100 selectively degrades the protein c-Myc over other proteins and effectively kills cancer cells that overexpress c-Myc [ 45 ]. Human triple-negative breast and gastric cancer xenografts have been demonstrated to regress in response to WZ-2–033, a new STAT3 inhibitor [ 46 ]. According to a study, a bromine domain and extra terminal domain inhibitor can induce tumor cell apoptosis by disrupting the specific transcription network that the TCF4 TF regulates [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis revealed the immunoinflammatory targets of rheumatoid arthritis based on intestinal flora, miRNA, transcription factors, and RNA-binding proteins databases, GSEA and GSVA pathway observations, and immunoinfiltration typing

Guan,

Zhang,

Zhao

et al. 2024

Hereditas

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Objective Rheumatoid arthritis (RA) is a chronic inflammatory arthritis. This study aimed to identify potential biomarkers and possible pathogenesis of RA using various bioinformatics analysis tools. Methods The GMrepo database provided a visual representation of the analysis of intestinal flora. We selected the GSE55235 and GSE55457 datasets from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) separately. With the intersection of these DEGs with the target genes associated with RA found in the GeneCards database, we obtained the DEGs targeted by RA (DERATGs). Subsequently, Disease Ontology, Gene Ontology, and the Kyoto Encyclopedia of Genes and Genomes were used to analyze DERATGs functionally. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed on the data from the gene expression matrix. Additionally, the protein-protein interaction network, transcription factor (TF)-targets, target-drug, microRNA (miRNA)-mRNA networks, and RNA-binding proteins (RBPs)-DERATGs correlation analyses were built. The CIBERSORT was used to evaluate the inflammatory immune state. The single-sample GSEA (ssGSEA) algorithm and differential analysis of DERATGs were used among the infiltration degree subtypes. Results There were some correlations between the abundance of gut flora and the prevalence of RA. A total of 54 DERATGs were identified, mainly related to immune and inflammatory responses and immunodeficiency diseases. Through GSEA and GSVA analysis, we found pathway alterations related to metabolic regulations, autoimmune diseases, and immunodeficiency-related disorders. We obtained 20 hub genes and 2 subnetworks. Additionally, we found that 39 TFs, 174 drugs, 2310 miRNAs, and several RBPs were related to DERATGs. Mast, plasma, and naive B cells differed during immune infiltration. We discovered DERATGs’ differences among subtypes using the ssGSEA algorithm and subtype grouping. Conclusions The findings of this study could help with RA diagnosis, prognosis, and targeted molecular treatment.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis revealed the immunoinflammatory targets of rheumatoid arthritis based on intestinal flora, miRNA, transcription factors, and RNA-binding proteins databases, GSEA and GSVA pathway observations, and immunoinfiltration typing

Guan,

Zhang,

Zhao

et al. 2024

Hereditas

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“…WZ-2–033, a novel STAT3 inhibitor, inhibits pY705-STAT3 phosphorylation, thereby reducing STAT3-dependent transcriptional activity and suppressing STAT3 expression from downstream genes. WZ-2–033 significantly suppressed the proliferation and tumorigenicity of TNBC in vivo and in vitro via blocking STAT3 activation [ 148 ].…”

Section: Tnbc-related Targeted Therapymentioning

confidence: 99%

Recent advances in targeted strategies for triple-negative breast cancer

Zhu,

Wu,

Song

et al. 2023

J Hematol Oncol

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Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, negatively expresses estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2 (HER2). Although chemotherapy is the main form of treatment for patients with TNBC, the effectiveness of chemotherapy for TNBC is still limited. The search for more effective therapies is urgent. Multiple targeted therapeutic strategies have emerged according to the specific molecules and signaling pathways expressed in TNBC. These include PI3K/AKT/mTOR inhibitors, epidermal growth factor receptor inhibitors, Notch inhibitors, poly ADP-ribose polymerase inhibitors, and antibody–drug conjugates. Moreover, immune checkpoint inhibitors, for example, pembrolizumab, atezolizumab, and durvalumab, are widely explored in the clinic. We summarize recent advances in targeted therapy and immunotherapy in TNBC, with the aim of serving as a reference for the development of individualized treatment of patients with TNBC in the future.

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“…2′-Methyl napabucasin is a synthetic furanonaphthoquinone analog that exhibited potent cytotoxicity against human keratinocytes [ 26 , 27 ]. In addition, napabucacin has been continuously considered as an anticancer agent in various targets, such as Akt/mTOR [ 28 ] and EGFR [ 29 ] involved in lung cancer and STAT3 associated with solid tumors [ 30 , 31 , 32 ]. However, its ability in JAK inhibitions has not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones

et al. 2023

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Janus kinases (JAKs) are involved in numerous cellular signaling processes related to immune cell functions. JAK2 and JAK3 are associated with the pathogenesis of leukemia and common lymphoid-derived illnesses. JAK2/3 inhibitors could reduce the risk of various diseases by targeting this pathway. Herein, the naphthoquinones were experimentally and theoretically investigated to identify novel JAK2/3 inhibitors. Napabucasin and 2′-methyl napabucasin exhibited potent cell growth inhibition in TF1 (IC50 = 9.57 and 18.10 μM) and HEL (IC50 = 3.31 and 6.65 μM) erythroleukemia cell lines, and they significantly inhibited JAK2/3 kinase activity (in a nanomolar range) better than the known JAK inhibitor, tofacitinib. Flow cytometric analysis revealed that these two compounds induced apoptosis in TF1 cells in a time and dose-dependent manner. From the molecular dynamics study, both compounds formed hydrogen bonds with Y931 and L932 residues and hydrophobically contacted with the conserved hinge region, G loop, and catalytic loop of the JAK2. Our obtained results suggested that napabucasin and its methylated analog were potential candidates for further development of novel anticancer drug targeting JAKs.

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The novel STAT3 inhibitor WZ-2-033 causes regression of human triple-negative breast cancer and gastric cancer xenografts

Cited by 18 publications

References 50 publications

Comprehensive analysis revealed the immunoinflammatory targets of rheumatoid arthritis based on intestinal flora, miRNA, transcription factors, and RNA-binding proteins databases, GSEA and GSVA pathway observations, and immunoinfiltration typing

Comprehensive analysis revealed the immunoinflammatory targets of rheumatoid arthritis based on intestinal flora, miRNA, transcription factors, and RNA-binding proteins databases, GSEA and GSVA pathway observations, and immunoinfiltration typing

Recent advances in targeted strategies for triple-negative breast cancer

In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones

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