A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

Bai, Longchuan; Zhou, Haibin; Xu, Renqi; Zhao, Yujun; Chinnaswamy, Krishnapriya; McEachern, Donna; Chen, Jianyong; Yang, Chao‐Yie; Liu, Zhaomin; Wang, Mi; Liu, Liu; Jiang, Hui; Wen, Bo; Kumar, Praveen; Meagher, Jennifer L.; Sun, Duxin; Stuckey, Jeanne A.; Wang, Shaomeng

doi:10.1016/j.ccell.2019.10.002

Cited by 380 publications

(342 citation statements)

References 97 publications

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“…The studies on PROTAC-mediated degradation of oncogenic proteins such as BRD4 [ 129 ], BCR-ABL [ 130 ], receptor tyrosine kinase (RTK) [ 131 ], and BCL-X L [ 132 ] have shown encouraging results, suggesting the potential clinical applicability of this ingenious approach. SD-36, a novel inhibitor identified by the PROTAC-based strategy, exhibits high selectivity for STAT3 and high cell permeability [ 98 ]. Moreover, SD-36 treatment can cause a profound and long-lasting suppression of tumor in mouse models of leukemia and lymphoma [ 98 ], suggesting that PROTAC-based strategy may be a promising and reliable avenue for searching small molecule inhibitors against STAT3.…”

Section: Targeting Stat3 For Cancer Immunotherapymentioning

confidence: 99%

Targeting STAT3 in Cancer Immunotherapy

et al. 2020

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As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for numerous cancers. In this review, we outline the importance of STAT3 signaling pathway in tumorigenesis and its immune regulation, and highlight the current status for the development of STAT3-targeting therapeutic approaches. We also summarize and discuss recent advances in STAT3-based combination immunotherapy in detail. These endeavors provide new insights into the translational application of STAT3 in cancer and may contribute to the promotion of more effective treatments toward malignancies.

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Section: Targeting Stat3 For Cancer Immunotherapymentioning

confidence: 99%

Targeting STAT3 in Cancer Immunotherapy

et al. 2020

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“…Several inhibitors of DNA binding proteins have been evaluated in clinical trials (Table 2). 34‐38 Signal transducer and activator of transcription 3 plays key roles in multiple cancer‐related signaling pathways and is aberrantly expressed in various human cancers 39 . Activation of STAT3 is associated with cancer stem cell properties such as tumor seeding ability and drug resistance 40,41 .…”

Section: Clinical Evaluation Of Small Molecule Inhibitors Targeting Dmentioning

confidence: 99%

Targeting DNA binding proteins for cancer therapy

et al. 2020

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Yoshitomo Shiroma and Ryou-u Takahashi contributed equally to this work.Abbreviations: AEP, AF4 family/ENL family/P-TEFb; ARNT, aryl hydrocarbon receptor nuclear translocator; BRD4, bromodomain-containing protein 4; CBP, CREB-binding protein; DUX4, double homeobox protein 4; ETO, eight-twenty one; EWS, Ewing's sarcoma; FLI1, friend leukemia virus integration 1; HIF, hypoxia-inducible factor; MLL, mixed-lineage leukemia; SOX2, Sry-related high-mobility box 2; STAT3, signal transducer and activator of transcription 3; TF, transcription factor; TRF, telomere-repeat binding factor. AbstractDysregulation or mutation of DNA binding proteins such as transcription factors (TFs) is associated with the onset and progression of various types of disease, including cancer. Alteration of TF activity occurs in numerous cancer tissues due to gene amplification, deletion, and point mutations, and epigenetic modification. Although cancer-associated TFs are promising targets for cancer therapy, development of drugs targeting these TFs has historically been difficult due to the lack of high-throughput screening methods. Recent advances in technology for identification and selective inhibition of DNA binding proteins enable cancer researchers to develop novel therapeutics targeting cancer-associated TFs. In the present review, we summarize known cancer-associated TFs according to cancer type and introduce recently developed high-throughput approaches to identify selective inhibitors of cancer-associated TFs. K E Y W O R D SDNA binding protein, drug discovery, high-throughput screening, telomere, transcription factor | 1059 SHIROMA et Al.

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“…Given that developing effective and selective inhibitors of STAT3 remains challenging, very recently, the Wang group developed potent and specific PROTAC degraders targeting STAT3 that showed great in vivo therapeutic potential for AML and anaplastic large-cell lymphoma (ALCL) 321 (Fig. 40).…”

Section: Stat3mentioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

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Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

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A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

Cited by 380 publications

References 97 publications

Targeting STAT3 in Cancer Immunotherapy

Targeting STAT3 in Cancer Immunotherapy

Targeting DNA binding proteins for cancer therapy

PROTACs: great opportunities for academia and industry

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