Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we?

Beebe, Jenny; Liu, Jing Yuan; Zhang, Jian-Ting

doi:10.1016/j.pharmthera.2018.06.006

Cited by 115 publications

(101 citation statements)

References 182 publications

(182 reference statements)

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“…To date, the direct targeting of STAT3 through small molecules remains the best option to achieve this goal. Unfortunately, issues related to the suboptimal efficacy and unfavorable pharmacokinetic properties of such compounds have limited their use in the clinic (Beebe et al, 2018). Antisense technology has recently emerged as a compelling therapeutic strategy to target difficult to hit proteins by downregulating their mRNA in several disease settings (Le et al, 2018;Marafini and Monteleone, 2018;Rinaldi and Wood, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, STAT3 is considered as an attractive therapeutic target in CRC (Yu et al, 2014). However, conventional approaches aimed at inhibiting STAT3 functions have been challenged by some limitations (Beebe et al, 2018). For instance, due to the high similarity of STAT3 with STAT1, a STAT family member involved in cell death and defense against pathogens (Avalle et al, 2012), STAT3 inhibitors can enhance the risk of infections (Nero et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Progranulin sustains STAT3 hyper‐activation and oncogenic function in colorectal cancer cells

et al. 2019

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Persistent activation of Signal Transducer and Activator of Transcription (STAT)3 occurs in a high percentage of tumors, including colorectal cancer (CRC), thereby contributing to malignant cell proliferation and survival. Although STAT3 is recognized as an attractive therapeutic target in CRC, conventional approaches aimed at inhibiting its functions have met with several limitations. Moreover, the factors that sustain hyper‐activation of STAT3 in CRC are not yet fully understood. The identification of tumor‐specific STAT3 cofactors may facilitate the development of compounds that interfere exclusively with STAT3 activity in cancer cells. Here, we show that progranulin, a STAT3 cofactor, is upregulated in human CRC as compared to nontumor tissue/cells and its expression correlates with STAT3 activation. Progranulin physically interacts with STAT3 in CRC cells, and its knockdown with a specific antisense oligonucleotide (ASO) inhibits STAT3 activation and restrains the expression of STAT3‐related oncogenic proteins, thus causing cell cycle arrest and apoptosis. Moreover, progranulin knockdown reduces STAT3 phosphorylation and cell proliferation induced by tumor‐infiltrating leukocyte (TIL)‐derived supernatants in CRC cell lines and human CRC explants. These findings indicate that CRC exhibits overexpression of progranulin, and suggest a role for this protein in amplifying the STAT3 pathway in CRC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Progranulin sustains STAT3 hyper‐activation and oncogenic function in colorectal cancer cells

et al. 2019

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“…To date, no STAT3 inhibitors have yet been approved to treat cancer by the Food and Drug Administration (FDA), but many early-phase clinical trials are ongoing [136]. AZD9150, an antisense oligonucleotide inhibitor of STAT3, inhibits STAT3 activation in ALCL and nonsmall cell lung cancer lines and demonstrates antitumor activity in lymphoma and lung cancer patient-derived xenograft models [137].…”

Section: Direct Stat3 Inhibitionmentioning

confidence: 99%

STAT3 Activation and Oncogenesis in Lymphoma

Zhu

Wang²,

2019

Cancers

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Signal transducer and activator of transcription 3 (STAT3) is an important and the most studied transcription factor in the Janus kinase (JAK)/STAT signaling pathway. STAT3 mediates the expression of various genes that play a critical role in many cellular and biological processes, such as cell proliferation, survival, differentiation, migration, angiogenesis, and inflammation. STAT3 and associated JAKs are activated and tightly regulated by a variety of cytokines and growth factors and their receptors in normal immune responses. However, abnormal expression of STAT3 leads to its constitutive activation, which promotes malignant transformation and tumor progression through oncogenic gene expression in numerous human cancers. Human lymphoma is a heterogeneous malignancy of T and B lymphocytes. Constitutive signaling by STAT3 is an oncogenic driver in several types of B-cell lymphoma and most of T-cell lymphomas. Aberrant STAT3 activation can also induce inappropriate expression of genes involved in tumor immune evasion such as PD-L1. In this review, we focus on the oncogenic role of STAT3 in human lymphoma and highlight potential therapeutic intervention by targeting JAK/STAT3 signaling.

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“…Although STAT3 inhibitors have mainly been developed as monotherapy to date, cancer cells can still utilize alternative salvage pathways such as the RAF/MEK/ERK and PI3K/AKT pathways that are also crucial in proliferation and survival in many cases 15 . Thus, we anticipated that blocking of the STAT3 pathway alone is insufficient to control tumor development and progression, and it is necessary to use STAT3 inhibitors in combination therapy 6,14 …”

Section: Introductionmentioning

confidence: 99%

Antitumor activity of a novel oral signal transducer and activator of transcription 3 inhibitor YHO‐1701

et al. 2020

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The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival and invasion. Aberrant STAT3 has been demonstrated in various malignant cancers. YHO-1701 is a novel quinolinecarboxamide derivative generated from STX-0119. Here, we examined the effect of YHO-1701 on STAT3 and evaluated antitumor activity of YHO-1701 as a single agent and in combination. YHO-1701 inhibited STAT3-SH2 binding to phospho-Tyr peptide selectively and more potently than STX-0119 in biochemical assays. Molecular docking studies with STAT3 suggested more stable interaction of YHO-1701 with the SH2 domain. YHO-1701 exhibited approximately 10-fold stronger activity than STX-0119 in abrogating the STAT3 signaling pathway of human oral cancer cell line SAS. YHO-1701 also blocked multi-step events by inhibiting STAT3 dimerization and suppressed STAT3 promoter activity. As expected, YHO-1701 exerted strong antiproliferative activity against human cancer cell lines addicted to STAT3 signaling. Orally administered YHO-1701 showed statistically significant antitumor effects with long exposure to high levels of YHO-1701 at tumor sites in SAS xenograft models. Moreover, combination regimen with sorafenib led to significantly stronger antitumor activity.In addition, the suppression level of survivin (a downstream target) was superior for the combination as compared with monotherapy groups within tumor tissues. Thus, YHO-1701 had a favorable specificity for STAT3 and pharmacokinetics after oral treatment; it also contributed to the enhanced antitumor activity of sorafenib. The evidence presented here provides justification using for this approach in future clinical settings. K E Y W O R D Scombination therapy, SH2 domain, signaling pathway, sorafenib, STAT3 inhibitor | 1775 NISHISAKA et Al.

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Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we?

Cited by 115 publications

References 182 publications

Progranulin sustains STAT3 hyper‐activation and oncogenic function in colorectal cancer cells

Progranulin sustains STAT3 hyper‐activation and oncogenic function in colorectal cancer cells

STAT3 Activation and Oncogenesis in Lymphoma

Antitumor activity of a novel oral signal transducer and activator of transcription 3 inhibitor YHO‐1701

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