Identification of a New Series of STAT3 Inhibitors by Virtual Screening

Matsuno, Kenji; Masuda, Yoshiaki; Uehara, Yutaka; Satō, Hiroshi; Muroya, Ayumu; Takahashi, Osamu; Yokotagawa, Takane; Furuya, Toshio; Okawara, Tadashi; Otsuka, Masami; Ogo, Naohisa; Ashizawa, Tadashi; Oshita, Chie; Tai, Sachiko; Ishii, Hidee; Akiyama, Yasuto; Asai, Akira

doi:10.1021/ml1000273

Cited by 132 publications

(104 citation statements)

References 24 publications

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“…our study revealed that StX-0119 had a potent growth-inhibitory effect on the human lymphoma cell line Scc3 (Stat3-activated), and effectively down-regulated downstream target genes of the Stat3 signaling pathway including c-myc, Bcl-xL, cyclin D1 and survivin without significantly affecting Stat3 phosphorylation. Matsuno et al (15) reported similar results from experiments in vitro using human breast cancer MDa-MB-468 cells. More impressively, StX-0119 exhibited stronger growth inhibition against Scc3 tumors in vivo than did ag490.…”

Section: Discussionmentioning

confidence: 58%

“…considering the high concentration of StX-0119 in mouse plasma after an oral administration in a pharmacokinetic study reported previously (15), there may be a discrepancy between the plasma concentration and antitumor effect. Poor uptake of StX-0119 in the tumor site and a weak immunological antitumor effect in nude mice triggered by overcoming the Stat3-mediated immunosuppression induced in the tumor microenvironment (37) may be responsible for this discrepancy.…”

Section: Discussionmentioning

confidence: 85%

“…Previously, we identified a novel small-molecule inhibitor of Stat3 dimerization, StX-0119, using biochemical and virtual screening methods (Stat3-dependent luciferase reporter gene assay and Stat3 dimerization assay using fret) for antagonizing the activity of Stat3-SH2 binding (15). the crystal structure of a Stat3-based computer model (in silico) obtained with a docking simulation algorithm named consensus-Dock revealed that StX-0119 binds directly to the SH2 region of the Stat3 monomer and antagonizes the dimerization.…”

Section: Discussionmentioning

confidence: 99%

“…Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation taDaSHi aSHiZaWa 1 6 , aKira aSai 2 and yaSuto aKiyaMa dimerization by simulating docking in silico and by screening for active compounds through biochemical methods and with in vitro as well as in vivo systems (15). in the present study we demonstrated the antitumor activity of a novel Stat3-SH2 antagonist, StX-0119, against a constitutively Stat3-activated human lymphoma cell line and investigated the mechanism responsible for the efficacy of StX-0119.…”

Section: Introductionmentioning

confidence: 99%

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Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation

Akiyama¹

2011

Int J Oncol

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Abstract. Signal transducer and activator of transcription (Stat)3, a member of a family of Dna-binding molecules mediating numerous physiological and oncogenic signaling pathways, is a novel target in cancer cells which show high phosphorylation of STAT3. Recently, we identified a novel small-molecule inhibitor of Stat3 dimerization, StX-0119, as a cancer therapeutic. We investigated the mechanisms responsible for the antitumor activity in vitro and in vivo through numerous biochemical and biological assays. Specifically, the effects of StX-0119 on target genes (c-myc, cyclin D1, survivin) and apoptosis induction were analyzed in tumors treated with StX-0119 in vivo. StX-0119 showed strong growth-inhibitory activity against a broad range of hematological cancer cell lines, particularly lymphomas. StX-0119 suppressed the growth of Scc3 cells, a human lymphoma cell line with highly activated Stat3, through apoptosis and down-regulation of Stat3 targets such as c-myc, cyclin D1, survivin and Bcl-xl. notably, tyr-705-phosphorylated Stat3 up-regulation was not significantly suppressed by STX-0119, as opposed to other Stat3 inhibitors. StX-0119 demonstrated potent antitumor effects in vivo in Scc3-bearing nude mice by way of the down-regulation of Stat3 target genes and induction of apoptosis in the tumors. thus, StX-0119 may be a new type of Stat3 inhibitor exhibiting strong antitumor activity. Introductionthe signal transducer and activator of transcription (Stat) protein family is a group of transcription factors that play an important role in relaying signals from growth factors and cytokines (1-3). Stat3 is reported to be involved in oncogenesis by up-regulating the transcription of several genes that control tumor cell survival, resistance to apoptosis, cell cycle progression and angiogenesis. targets of Stat3 include Bcl-2 (4), Bcl-xl (5), c-myc (6), cyclin D1 (7), vascular endothelial growth factor (8) and human telomerase reverse transcriptase (9).Several Stats have been associated with the proliferation and survival of cancer cells; however Stat3 is also widely expressed in normal cells. generally, Stat3 is temporarily activated in a manner strictly regulated by the protein inhibitor of Stats (PiaS), Src homology (SH)2-containing tyrosine phosphatases (SHP1 and SHP2) (10), and suppressor of cytokine signaling/extracellular signal-regulated kinase (SOCS/ERK) (11) to protect cells from excess inflammatory signaling.Moreover, persistent activation of Stat3 occurs in many hematological malignancies (12,13) and solid cancers. constitutive Stat3 activation up-regulates the expression of anti-apoptotic factors including Bcl-xl, Bcl-2 and Mcl-1 and promotes the survival of tumor cells, thus contributing to resistance to faS-or chemotherapy-induced apoptosis (14). Blocking of STAT3 signaling demonstrated significant growth inhibition of cancer cells by down-regulation of the expression of anti-apoptotic genes, leading to apoptosis. the activation of Stat3 occurs when it is phosphorylated at the tyr-705 residue. this...

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation

Akiyama¹

2011

Int J Oncol

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“…Recently, a series of novel STAT3 dimerization inhibitors was discovered through an SBVS campaign [213]. A database containing millions of compounds was filtered for drug-like properties, resulting in a final collection of approximately 360,000 molecules, which was then used in the SBVS.…”

Section: Identification Of a New Series Of Stat3 Inhibitors By Vsmentioning

confidence: 99%

Molecular Docking and Structure-Based Drug Design Strategies

et al. 2015

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Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. This approach also estimates the ligand-receptor binding free energy by evaluating critical phenomena involved in the intermolecular recognition process. Today, as a variety of docking algorithms are available, an understanding of the advantages and limitations of each method is of fundamental importance in the development of effective strategies and the generation of relevant results. The purpose of this review is to examine current molecular docking strategies used in drug discovery and medicinal chemistry, exploring the advances in the field and the role played by the integration of structure-and ligand-based methods.

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Docking, Scoring, and Virtual Screening in Drug Discovery

Spyrakis

Sarkar

Kellogg

2021

Burger's Medicinal Chemistry and Drug Discovery

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Since its introduction about four decades ago, docking and scoring are now the very heart of structure‐based drug design. The past 10–20 years have seen a plethora of docking and scoring tools successfully integrated into drug discovery pipelines. Interestingly, while artificial intelligence is now receiving significant attention in the computational modeling arena, docking and scoring have long utilized these techniques. This comprehensive summary highlights some of the most significant achievements of docking and scoring, reviews the current status, provides descriptions of many of the tools available, comments on some of the outstanding challenges facing the paradigm, and offers perspectives and advice on best practices for users. While significant development is still needed in docking of flexible molecules and accurate Gibb's free energy predictions, docking and scoring are very useful when handled by experienced practitioners, but less so if treated as a “black box.” Lastly, we present a hypothetical case so beginners may appreciate the nuances of setting up a docking study. Focus in docking is now shifting toward parallel applications, i.e. protein–protein, protein–oligosaccharide, protein–DNA, or protein–RNA docking and polypharmacology. In summary, this article is intended to elucidate the nuances of the subject, while providing guidelines for practical implementation of effective workflows in drug discovery and structural biology.

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Identification of a New Series of STAT3 Inhibitors by Virtual Screening

Cited by 132 publications

References 24 publications

Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation

Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation

Molecular Docking and Structure-Based Drug Design Strategies

Docking, Scoring, and Virtual Screening in Drug Discovery

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