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Therapeutic modulators of STAT signalling for human diseases

Key Points

  • Considerable evidence supports the crucial roles of the signal transducer and activator of transcription (STAT) family of proteins in human diseases, particularly in immune and inflammatory disorders, infection and cancer

  • Increasing emphasis is being placed on developing direct STAT inhibitors for clinical application, mainly through the discovery of small molecules, oligonucleotides and natural product derivatives.

  • A large part of the ongoing STATs drug discovery research for therapeutics is focused on targeting STAT3, of which the efforts to develop small-molecule STAT3 inhibitors is extensive. While research into oligodeoxynucleotide (ODN) decoys and antisense oligonucleotides (ASOs) as STAT-inhibitory approaches is not as widespread, these efforts appear to be advancing as a STAT3 ODN has progressed to clinical trials (Phase 0).

  • Tyrosine kinase inhibitors (TKIs) as therapeutic modalities are widely explored, and this approach is highly established. TKI agents may be therapeutic considerations in STAT-associated diseases in so far as a causal link could be established between the target tyrosine kinase and dysregulated STAT signalling that is prevalent in the disease.

  • The precedence of natural product-based therapeutics for many diseases and the number of reports on natural product inhibitors of STAT3 signalling together highlight the potential of this resource as an important source of leads for developing STAT inhibitors.

  • There is a clinical trial to evaluate ISIS-STAT3Rx ASO against advanced cancers. Other clinical trials are focusing on therapeutic modalities that can affect STAT function and STAT-associated diseases, including the evaluation of curcumin for pancreatic cancer, resveratrol for colorectal cancer and 3,3′-diindolylmethane for breast cancer, and TKIs against many cancer types.

Abstract

The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials.

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Figure 1: A schematic representation of the structures of the STAT proteins.
Figure 2: STAT signalling pathway, functions and associated diseases.
Figure 3: Models of inhibition of STAT signalling.

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Acknowledgements

The authors thank all their colleagues and members of their laboratory for the stimulating discussions related to this work. The authors also thank A. Chelsky for the art work for figure 3. This work was supported by grants from the National Cancer Institute (CA128865 and CA161931) and from the University of Hawaii to J.T.

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Miklossy, G., Hilliard, T. & Turkson, J. Therapeutic modulators of STAT signalling for human diseases. Nat Rev Drug Discov 12, 611–629 (2013). https://doi.org/10.1038/nrd4088

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