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Brent D. G. Page - One of the best experts on this subject based on the ideXlab platform.
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STAT3 differential scanning fluorimetry and differential scanning light scattering assays: Addressing a missing link in the characterization of STAT3 inhibitor interactions.
Journal of pharmaceutical and biomedical analysis, 2018Co-Authors: Matthieu Desroses, Sander Busker, Juan Astorga-wells, Sanaz Attarha, Iryna Kolosenko, Roman A. Zubarev, Thomas Helleday, Dan Grandér, Brent D. G. PageAbstract:STAT3 Protein is an established target for the development of new cancer therapeutic agents. Despite lacking a traditional binding site for small molecule inhibitors, many STAT3 inhibitors have been identified and explored for their anti-cancer activity. Because STAT3 signaling is mediated by Protein-Protein interactions, indirect methods are often employed to determine if proposed STAT3 inhibitors bind to STAT3 Protein. While established STAT3 inhibition assays (such as the fluorescence polarization assay, electrophoretic mobility shift assay and ELISAs) have been used to identify novel inhibitors of STAT3 signaling, methods that directly assess STAT3 Protein-inhibitor interactions could facilitate the development of novel inhibitors. In this context, we herein report new STAT3 binding assays based on differential scanning fluorimetry (DSF) and differential scanning light scattering (DSLS) to characterize interactions between STAT3 Protein and inhibitors. Several peptide and small molecule STAT3 inhibitors have been evaluated, and new insight into how these compounds may interact with STAT3 is provided.
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Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics
Molecular cancer therapeutics, 2016Co-Authors: Carolynn C. Arpin, Brent D. G. Page, Stephen Mac, Yanlin Jiang, Huiwen Cheng, Michelle Grimard, Malgorzata M. Kamocka, Sina Haftchenary, Daniel P. BallAbstract:Constitutively activated STAT3 Protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study, PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low micromolar range. PG-S3-001 binds the STAT3 Protein potently, Kd = 324 nmol/L by surface plasmon resonance, and showed no effect in a kinome screen (>100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized three-dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAF). In this coculture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D cocultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells. Mol Cancer Ther; 15(5); 794-805. ©2016 AACR.
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Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma
ACS medicinal chemistry letters, 2013Co-Authors: Sina Haftchenary, Brent D. G. Page, Vijay M. Shahani, Hema Artee Luchman, Andriana O. Jouk, Anthony J. Veloso, Xin R. Cheng, Grinshtein N, Kagan KermanAbstract:The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 Protein (KD = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood–brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application.
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identification of a non phosphorylated cell permeable small molecule ligand for the STAT3 sh2 domain
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Brent D. G. Page, Steven Fletcher, Sumaiya Sharmeen, Suzanne Trudel, Xiaolei Zhang, Zhi Hua Li, Alessandro Datti, Jeffrey L Wrana, Aaron D. SchimmerAbstract:Abstract Signal transducer and activator of transcription 3 (STAT3) Protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated STAT3–STAT3 Protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated STAT3. Herein, we report the design and synthesis of a focused library of salicylic acid containing STAT3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted STAT3–phosphopeptide complexes (Ki = 13 μM), inhibited STAT3–STAT3 Protein interactions (IC50 = 19 μM) and silenced intracellular STAT3 phosphorylation and STAT3-target gene expression profiles. Inhibition of STAT3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC50 = 10 and 16 μM, respectively).
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antagonism of the STAT3 STAT3 Protein dimer with salicylic acid based small molecules
ChemMedChem, 2011Co-Authors: Steven Fletcher, Brent D. G. Page, Xialoei Zhang, Peibin Yue, Sumaiya Sharmeen, Jagdeep Singh, Wei Zhao, Aaron D. Schimmer, Suzanne Trudel, James TurksonAbstract:More than 50 new inhibitors of the oncogenic STAT3 Protein were identified through a structure-activity relationship (SAR) study based on the previously identified inhibitor S3I-201 (IC₅₀ =86 μM, K(i) >300 μM). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the STAT3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting STAT3 DNA binding activity, with an in vitro IC₅₀ range of 18.7-51.9 μM, and disruption of STAT3-pTyr peptide interactions with K(i) values in the 15.5-41 μM range. One agent in particular exhibited potent inhibition of STAT3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of STAT3 target genes, and induced antitumor effects in tumor cells harboring activated STAT3 Protein.
Steven Fletcher - One of the best experts on this subject based on the ideXlab platform.
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identification of a non phosphorylated cell permeable small molecule ligand for the STAT3 sh2 domain
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Brent D. G. Page, Steven Fletcher, Sumaiya Sharmeen, Suzanne Trudel, Xiaolei Zhang, Zhi Hua Li, Alessandro Datti, Jeffrey L Wrana, Aaron D. SchimmerAbstract:Abstract Signal transducer and activator of transcription 3 (STAT3) Protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated STAT3–STAT3 Protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated STAT3. Herein, we report the design and synthesis of a focused library of salicylic acid containing STAT3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted STAT3–phosphopeptide complexes (Ki = 13 μM), inhibited STAT3–STAT3 Protein interactions (IC50 = 19 μM) and silenced intracellular STAT3 phosphorylation and STAT3-target gene expression profiles. Inhibition of STAT3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC50 = 10 and 16 μM, respectively).
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antagonism of the STAT3 STAT3 Protein dimer with salicylic acid based small molecules
ChemMedChem, 2011Co-Authors: Steven Fletcher, Brent D. G. Page, Xialoei Zhang, Peibin Yue, Sumaiya Sharmeen, Jagdeep Singh, Wei Zhao, Aaron D. Schimmer, Suzanne Trudel, James TurksonAbstract:More than 50 new inhibitors of the oncogenic STAT3 Protein were identified through a structure-activity relationship (SAR) study based on the previously identified inhibitor S3I-201 (IC₅₀ =86 μM, K(i) >300 μM). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the STAT3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting STAT3 DNA binding activity, with an in vitro IC₅₀ range of 18.7-51.9 μM, and disruption of STAT3-pTyr peptide interactions with K(i) values in the 15.5-41 μM range. One agent in particular exhibited potent inhibition of STAT3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of STAT3 target genes, and induced antitumor effects in tumor cells harboring activated STAT3 Protein.
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Antagonism of the STAT3–STAT3 Protein Dimer with Salicylic Acid Based Small Molecules
ChemMedChem, 2011Co-Authors: Steven Fletcher, Brent D. G. Page, Xialoei Zhang, Peibin Yue, Sumaiya Sharmeen, Jagdeep Singh, Wei Zhao, Aaron D. Schimmer, Suzanne TrudelAbstract:More than 50 new inhibitors of the oncogenic STAT3 Protein were identified through a structure-activity relationship (SAR) study based on the previously identified inhibitor S3I-201 (IC₅₀ =86 μM, K(i) >300 μM). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the STAT3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting STAT3 DNA binding activity, with an in vitro IC₅₀ range of 18.7-51.9 μM, and disruption of STAT3-pTyr peptide interactions with K(i) values in the 15.5-41 μM range. One agent in particular exhibited potent inhibition of STAT3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of STAT3 target genes, and induced antitumor effects in tumor cells harboring activated STAT3 Protein.
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Design, Synthesis and in vitro Characterization of Novel Hybrid Peptidomimetic Inhibitors of STAT3 Protein
Bioorganic & medicinal chemistry, 2010Co-Authors: Vijay M. Shahani, Steven Fletcher, Peibin Yue, Sumaiya Sharmeen, Wei Zhao, Mahadeo A. Sukhai, Diana P. Luu, Xiaolei Zhang, Hong Sun, Aaron D. SchimmerAbstract:Aberrant activation of oncogenic signal transducer and activator of transcription 3 (STAT3) Protein signaling pathways has been extensively implicated in human cancers. Given STAT3’s prominent dysregulatory role in malignant transformation and tumorigenesis, there has been a significant effort to discover STAT3-specific inhibitors as chemical probes for defining the aberrant STAT3-mediated molecular events that support the malignant phenotype. To identify novel, STAT3-selective inhibitors suitable for interrogating STAT3 signaling in tumor cells, we explored the design of hybrid molecules by conjugating a known STAT3 inhibitory peptidomimetic, ISS610 to the high-affinity STAT3-binding peptide motif derived from the ILR/gp-130. Several hybrid molecules were examined in in vitro biophysical and biochemical studies for inhibitory potency against STAT3. Lead inhibitor 14aa was shown to strongly bind to STAT3 (KD = 900 nM), disrupt STAT3:phosphopeptide complexes (Ki = 5 μM) and suppress STAT3 activity in in vitro DNA-binding activity/ electrophoretic mobility shift assay (EMSA). Moreover, lead STAT3 inhibitor 14aa induced a time-dependent inhibition of constitutive STAT3 activation in v-Src transformed mouse fibroblasts (NIH3T3/v-Src), with 80 % suppression of constitutively-active STAT3 at six hours following treatment of NIH3T3/v-Src. However, STAT3 activity recovered at 24 hours after treatment of cells, suggesting potential degradation of the compound. Results further showed a suppression of aberrant STAT3 activity in NIH3T3/v-Src by the treatment with compound 14aa-OH, which is the non-pTyr version of compound 14aa. The effect of compounds 14aa and 14aa-OH are accompanied by a moderate loss of cell viability.
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coordination complex sh2 domain proteomimetics an alternative approach to disrupting oncogenic Protein Protein interactions
Chemical Communications, 2010Co-Authors: Joel A. Drewry, Steven Fletcher, Peibin Yue, Sumaiya Sharmeen, Wei Zhao, Aaron D. Schimmer, Xiaolei Zhang, Denys O Marushchak, Claudiu C Gradinaru, James TurksonAbstract:We report the first application of coordination complexes as functional proteomimetics of the Src homology 2 (SH2) phosphopeptide-binding domain. As a proof-of-concept, functionalized bis-dipicolylamine (BDPA) copper(II) complexes are shown to disrupt oncogenic STAT3–STAT3 Protein complexes and elicit promising anti-tumour activity.
Aaron D. Schimmer - One of the best experts on this subject based on the ideXlab platform.
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identification of a non phosphorylated cell permeable small molecule ligand for the STAT3 sh2 domain
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Brent D. G. Page, Steven Fletcher, Sumaiya Sharmeen, Suzanne Trudel, Xiaolei Zhang, Zhi Hua Li, Alessandro Datti, Jeffrey L Wrana, Aaron D. SchimmerAbstract:Abstract Signal transducer and activator of transcription 3 (STAT3) Protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated STAT3–STAT3 Protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated STAT3. Herein, we report the design and synthesis of a focused library of salicylic acid containing STAT3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted STAT3–phosphopeptide complexes (Ki = 13 μM), inhibited STAT3–STAT3 Protein interactions (IC50 = 19 μM) and silenced intracellular STAT3 phosphorylation and STAT3-target gene expression profiles. Inhibition of STAT3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC50 = 10 and 16 μM, respectively).
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antagonism of the STAT3 STAT3 Protein dimer with salicylic acid based small molecules
ChemMedChem, 2011Co-Authors: Steven Fletcher, Brent D. G. Page, Xialoei Zhang, Peibin Yue, Sumaiya Sharmeen, Jagdeep Singh, Wei Zhao, Aaron D. Schimmer, Suzanne Trudel, James TurksonAbstract:More than 50 new inhibitors of the oncogenic STAT3 Protein were identified through a structure-activity relationship (SAR) study based on the previously identified inhibitor S3I-201 (IC₅₀ =86 μM, K(i) >300 μM). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the STAT3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting STAT3 DNA binding activity, with an in vitro IC₅₀ range of 18.7-51.9 μM, and disruption of STAT3-pTyr peptide interactions with K(i) values in the 15.5-41 μM range. One agent in particular exhibited potent inhibition of STAT3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of STAT3 target genes, and induced antitumor effects in tumor cells harboring activated STAT3 Protein.
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Antagonism of the STAT3–STAT3 Protein Dimer with Salicylic Acid Based Small Molecules
ChemMedChem, 2011Co-Authors: Steven Fletcher, Brent D. G. Page, Xialoei Zhang, Peibin Yue, Sumaiya Sharmeen, Jagdeep Singh, Wei Zhao, Aaron D. Schimmer, Suzanne TrudelAbstract:More than 50 new inhibitors of the oncogenic STAT3 Protein were identified through a structure-activity relationship (SAR) study based on the previously identified inhibitor S3I-201 (IC₅₀ =86 μM, K(i) >300 μM). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the STAT3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting STAT3 DNA binding activity, with an in vitro IC₅₀ range of 18.7-51.9 μM, and disruption of STAT3-pTyr peptide interactions with K(i) values in the 15.5-41 μM range. One agent in particular exhibited potent inhibition of STAT3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of STAT3 target genes, and induced antitumor effects in tumor cells harboring activated STAT3 Protein.
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Design, Synthesis and in vitro Characterization of Novel Hybrid Peptidomimetic Inhibitors of STAT3 Protein
Bioorganic & medicinal chemistry, 2010Co-Authors: Vijay M. Shahani, Steven Fletcher, Peibin Yue, Sumaiya Sharmeen, Wei Zhao, Mahadeo A. Sukhai, Diana P. Luu, Xiaolei Zhang, Hong Sun, Aaron D. SchimmerAbstract:Aberrant activation of oncogenic signal transducer and activator of transcription 3 (STAT3) Protein signaling pathways has been extensively implicated in human cancers. Given STAT3’s prominent dysregulatory role in malignant transformation and tumorigenesis, there has been a significant effort to discover STAT3-specific inhibitors as chemical probes for defining the aberrant STAT3-mediated molecular events that support the malignant phenotype. To identify novel, STAT3-selective inhibitors suitable for interrogating STAT3 signaling in tumor cells, we explored the design of hybrid molecules by conjugating a known STAT3 inhibitory peptidomimetic, ISS610 to the high-affinity STAT3-binding peptide motif derived from the ILR/gp-130. Several hybrid molecules were examined in in vitro biophysical and biochemical studies for inhibitory potency against STAT3. Lead inhibitor 14aa was shown to strongly bind to STAT3 (KD = 900 nM), disrupt STAT3:phosphopeptide complexes (Ki = 5 μM) and suppress STAT3 activity in in vitro DNA-binding activity/ electrophoretic mobility shift assay (EMSA). Moreover, lead STAT3 inhibitor 14aa induced a time-dependent inhibition of constitutive STAT3 activation in v-Src transformed mouse fibroblasts (NIH3T3/v-Src), with 80 % suppression of constitutively-active STAT3 at six hours following treatment of NIH3T3/v-Src. However, STAT3 activity recovered at 24 hours after treatment of cells, suggesting potential degradation of the compound. Results further showed a suppression of aberrant STAT3 activity in NIH3T3/v-Src by the treatment with compound 14aa-OH, which is the non-pTyr version of compound 14aa. The effect of compounds 14aa and 14aa-OH are accompanied by a moderate loss of cell viability.
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coordination complex sh2 domain proteomimetics an alternative approach to disrupting oncogenic Protein Protein interactions
Chemical Communications, 2010Co-Authors: Joel A. Drewry, Steven Fletcher, Peibin Yue, Sumaiya Sharmeen, Wei Zhao, Aaron D. Schimmer, Xiaolei Zhang, Denys O Marushchak, Claudiu C Gradinaru, James TurksonAbstract:We report the first application of coordination complexes as functional proteomimetics of the Src homology 2 (SH2) phosphopeptide-binding domain. As a proof-of-concept, functionalized bis-dipicolylamine (BDPA) copper(II) complexes are shown to disrupt oncogenic STAT3–STAT3 Protein complexes and elicit promising anti-tumour activity.
James Turkson - One of the best experts on this subject based on the ideXlab platform.
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antagonism of the STAT3 STAT3 Protein dimer with salicylic acid based small molecules
ChemMedChem, 2011Co-Authors: Steven Fletcher, Brent D. G. Page, Xialoei Zhang, Peibin Yue, Sumaiya Sharmeen, Jagdeep Singh, Wei Zhao, Aaron D. Schimmer, Suzanne Trudel, James TurksonAbstract:More than 50 new inhibitors of the oncogenic STAT3 Protein were identified through a structure-activity relationship (SAR) study based on the previously identified inhibitor S3I-201 (IC₅₀ =86 μM, K(i) >300 μM). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the STAT3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting STAT3 DNA binding activity, with an in vitro IC₅₀ range of 18.7-51.9 μM, and disruption of STAT3-pTyr peptide interactions with K(i) values in the 15.5-41 μM range. One agent in particular exhibited potent inhibition of STAT3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of STAT3 target genes, and induced antitumor effects in tumor cells harboring activated STAT3 Protein.
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coordination complex sh2 domain proteomimetics an alternative approach to disrupting oncogenic Protein Protein interactions
Chemical Communications, 2010Co-Authors: Joel A. Drewry, Steven Fletcher, Peibin Yue, Sumaiya Sharmeen, Wei Zhao, Aaron D. Schimmer, Xiaolei Zhang, Denys O Marushchak, Claudiu C Gradinaru, James TurksonAbstract:We report the first application of coordination complexes as functional proteomimetics of the Src homology 2 (SH2) phosphopeptide-binding domain. As a proof-of-concept, functionalized bis-dipicolylamine (BDPA) copper(II) complexes are shown to disrupt oncogenic STAT3–STAT3 Protein complexes and elicit promising anti-tumour activity.
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Resveratrol inhibits Src and STAT3 signaling and induces the apoptosis of malignant cells containing activated STAT3 Protein
Molecular cancer therapeutics, 2006Co-Authors: Anupama Kotha, James Turkson, Madhavi Sekharam, Lucia Cilenti, Khandaker Siddiquee, Annette R. Khaled, Antonis S. Zervos, Bradford Carter, Richard JoveAbstract:Resveratrol is a naturally occurring phytoalexin with antioxidant and antiinflammatory properties. Recent studies suggest that resveratrol possesses anticancer effects, although its mechanism of action is not well understood. We now show that resveratrol inhibits Src tyrosine kinase activity and thereby blocks constitutive signal transducer and activator of transcription 3 (STAT3) Protein activation in malignant cells. Analyses of resveratrol-treated malignant cells harboring constitutively-active STAT3 reveal irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human breast (MDA-MB-231), pancreatic (Panc-1), and prostate carcinoma (DU145) cell lines at the G-G1 phase or at the S phase of human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and loss of viability due to apoptosis. By contrast, cells treated with resveratrol, but lacking aberrant STAT3 activity, show reversible growth arrest and minimal loss of viability. Moreover, in malignant cells harboring constitutively-active STAT3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol treatment represses STAT3-regulated cyclin D1 as well as Bcl-xL and Mcl-1 genes, suggesting that the antitumor cell activity of resveratrol is in part due to the blockade of STAT3-mediated dysregulation of growth and survival pathways. Our study is among the first to identify Src-STAT3 signaling as a target of resveratrol, further defining the mechanism of antitumor cell activity of resveratrol and raising its potential application in tumors with an activated STAT3 profile. [Mol Cancer Ther 2006;5(3):621–9]
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constitutive STAT3 activity up regulates vegf expression and tumor angiogenesis
Oncogene, 2002Co-Authors: Guilian Niu, James Turkson, Kenneth L Wright, Mei Huang, Lanxi Song, Eric B Haura, Shumin M Zhang, Tianhong Wang, Dominic Sinibaldi, Domenico CoppolaAbstract:Non-receptor and receptor tyrosine kinases, such as Src and EGF receptor (EGFR), are major inducers of vascular endothelial growth factor (VEGF), one of the most potent mediators of angiogenesis. While tyrosine kinases signal through multiple pathways, signal transducer and activation of transcription 3 (STAT3) is a point of convergence for many of these and is constitutively activated with high frequency in a wide range of cancer cells. Here, we show that VEGF expression correlates with STAT3 activity in diverse human cancer cell lines. An activated STAT3 mutant (STAT3C) up-regulates VEGF expression and stimulates tumor angiogenesis. STAT3C-induced VEGF up-regulation is abrogated when a STAT3-binding site in the VEGF promoter is mutated. Furthermore, interrupting STAT3 signaling with dominant-negative STAT3 Protein or STAT3 antisense oligonucleotide in tumor cells down-regulates VEGF expression. Consistent with an important role of STAT3 in VEGF up-regulation induced by various oncogenic tyrosine kinases, v-Src-mediated VEGF expression is inhibited when STAT3 signaling is blocked. Moreover, chromatin immunoprecipitation assays indicate that STAT3 Protein binds to the VEGF promoter in vivo and mutation of a STAT3-binding site in the VEGF promoter abrogates v-Src-induced VEGF promoter activity. These studies provide evidence that the VEGF gene is regulated directly by STAT3 Protein, and indicate that STAT3 represents a common molecular target for blocking angiogenesis induced by multiple signaling pathways in human cancers.
Sumaiya Sharmeen - One of the best experts on this subject based on the ideXlab platform.
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identification of a non phosphorylated cell permeable small molecule ligand for the STAT3 sh2 domain
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Brent D. G. Page, Steven Fletcher, Sumaiya Sharmeen, Suzanne Trudel, Xiaolei Zhang, Zhi Hua Li, Alessandro Datti, Jeffrey L Wrana, Aaron D. SchimmerAbstract:Abstract Signal transducer and activator of transcription 3 (STAT3) Protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated STAT3–STAT3 Protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated STAT3. Herein, we report the design and synthesis of a focused library of salicylic acid containing STAT3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted STAT3–phosphopeptide complexes (Ki = 13 μM), inhibited STAT3–STAT3 Protein interactions (IC50 = 19 μM) and silenced intracellular STAT3 phosphorylation and STAT3-target gene expression profiles. Inhibition of STAT3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC50 = 10 and 16 μM, respectively).
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antagonism of the STAT3 STAT3 Protein dimer with salicylic acid based small molecules
ChemMedChem, 2011Co-Authors: Steven Fletcher, Brent D. G. Page, Xialoei Zhang, Peibin Yue, Sumaiya Sharmeen, Jagdeep Singh, Wei Zhao, Aaron D. Schimmer, Suzanne Trudel, James TurksonAbstract:More than 50 new inhibitors of the oncogenic STAT3 Protein were identified through a structure-activity relationship (SAR) study based on the previously identified inhibitor S3I-201 (IC₅₀ =86 μM, K(i) >300 μM). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the STAT3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting STAT3 DNA binding activity, with an in vitro IC₅₀ range of 18.7-51.9 μM, and disruption of STAT3-pTyr peptide interactions with K(i) values in the 15.5-41 μM range. One agent in particular exhibited potent inhibition of STAT3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of STAT3 target genes, and induced antitumor effects in tumor cells harboring activated STAT3 Protein.
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Antagonism of the STAT3–STAT3 Protein Dimer with Salicylic Acid Based Small Molecules
ChemMedChem, 2011Co-Authors: Steven Fletcher, Brent D. G. Page, Xialoei Zhang, Peibin Yue, Sumaiya Sharmeen, Jagdeep Singh, Wei Zhao, Aaron D. Schimmer, Suzanne TrudelAbstract:More than 50 new inhibitors of the oncogenic STAT3 Protein were identified through a structure-activity relationship (SAR) study based on the previously identified inhibitor S3I-201 (IC₅₀ =86 μM, K(i) >300 μM). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the STAT3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting STAT3 DNA binding activity, with an in vitro IC₅₀ range of 18.7-51.9 μM, and disruption of STAT3-pTyr peptide interactions with K(i) values in the 15.5-41 μM range. One agent in particular exhibited potent inhibition of STAT3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of STAT3 target genes, and induced antitumor effects in tumor cells harboring activated STAT3 Protein.
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Design, Synthesis and in vitro Characterization of Novel Hybrid Peptidomimetic Inhibitors of STAT3 Protein
Bioorganic & medicinal chemistry, 2010Co-Authors: Vijay M. Shahani, Steven Fletcher, Peibin Yue, Sumaiya Sharmeen, Wei Zhao, Mahadeo A. Sukhai, Diana P. Luu, Xiaolei Zhang, Hong Sun, Aaron D. SchimmerAbstract:Aberrant activation of oncogenic signal transducer and activator of transcription 3 (STAT3) Protein signaling pathways has been extensively implicated in human cancers. Given STAT3’s prominent dysregulatory role in malignant transformation and tumorigenesis, there has been a significant effort to discover STAT3-specific inhibitors as chemical probes for defining the aberrant STAT3-mediated molecular events that support the malignant phenotype. To identify novel, STAT3-selective inhibitors suitable for interrogating STAT3 signaling in tumor cells, we explored the design of hybrid molecules by conjugating a known STAT3 inhibitory peptidomimetic, ISS610 to the high-affinity STAT3-binding peptide motif derived from the ILR/gp-130. Several hybrid molecules were examined in in vitro biophysical and biochemical studies for inhibitory potency against STAT3. Lead inhibitor 14aa was shown to strongly bind to STAT3 (KD = 900 nM), disrupt STAT3:phosphopeptide complexes (Ki = 5 μM) and suppress STAT3 activity in in vitro DNA-binding activity/ electrophoretic mobility shift assay (EMSA). Moreover, lead STAT3 inhibitor 14aa induced a time-dependent inhibition of constitutive STAT3 activation in v-Src transformed mouse fibroblasts (NIH3T3/v-Src), with 80 % suppression of constitutively-active STAT3 at six hours following treatment of NIH3T3/v-Src. However, STAT3 activity recovered at 24 hours after treatment of cells, suggesting potential degradation of the compound. Results further showed a suppression of aberrant STAT3 activity in NIH3T3/v-Src by the treatment with compound 14aa-OH, which is the non-pTyr version of compound 14aa. The effect of compounds 14aa and 14aa-OH are accompanied by a moderate loss of cell viability.
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coordination complex sh2 domain proteomimetics an alternative approach to disrupting oncogenic Protein Protein interactions
Chemical Communications, 2010Co-Authors: Joel A. Drewry, Steven Fletcher, Peibin Yue, Sumaiya Sharmeen, Wei Zhao, Aaron D. Schimmer, Xiaolei Zhang, Denys O Marushchak, Claudiu C Gradinaru, James TurksonAbstract:We report the first application of coordination complexes as functional proteomimetics of the Src homology 2 (SH2) phosphopeptide-binding domain. As a proof-of-concept, functionalized bis-dipicolylamine (BDPA) copper(II) complexes are shown to disrupt oncogenic STAT3–STAT3 Protein complexes and elicit promising anti-tumour activity.