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Historical Development of STAT3 Inhibitors and Early Results in Clinical Trials

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STAT Inhibitors in Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Since the initial reports of constitutive STAT3 activation in cells transformed by viral oncoproteins, the critical role of STAT3 signaling in human cancers has been firmly established. Detailed understanding of how STAT3 activity is tightly regulated by the balance between activating and inhibitory circuits provides important insights of how STAT3 becomes deregulated in cancer cells. A large number of STAT3 inhibitors have been developed. The predominant emphasis of the early rational drug discovery strategies was on disrupting phospho-tyrosine (pY) interactions with the Src-homology 2 (SH2) domain due to its requirement for STAT3:STAT3 dimerization and STAT3 function. Following the first reported direct STAT3 inhibitor peptide, PpYLKTK and its derivatives and peptidomimetics, several other peptides, peptide mimetics, and small molecules have been developed. However, their slow clinical development is in a large part due to the significant challenges of targeting transcription factors by disrupting protein:protein interactions. Two other major strategies to directly target STAT3 signaling are the decoy oligodeoxynucleotide (ODN) and antisense oligonucleotide (ASO) approaches, which have their own challenges for clinical development relating to their physicochemcial properties. Moreover, a large variety of natural products have been found to inhibit STAT3 signaling pathways and tumor growth, although their precise mechanisms of action are often unclear. Tyrosine kinase inhibitors (TKIs), which impact STAT3 signaling indirectly through their inibitory effects on tyrosine phosphorylation, are the most advanced in clinical trials to date. Several TKIs are at various stages of clincal evaluation for safety and efficacy.

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Authors and Affiliations

  1. Department of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wenhua 1st Road, Taoyuan City, 33302, Taiwan, ROC

    Chao-Lan Yu

  2. Division of Hematology, Chang Gung Memorial Hospital, Taoyuan City, Linkou, Taiwan

    Chao-Lan Yu

  3. Cell Therapy Institute, Nova Southeastern University, 3301 College Avenue, Fort Lauderdale, FL, 33314, USA

    Richard Jove

  4. Cancer Biology and Natural Products and Experimental Therapeutics Programs, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA

    James Turkson

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  1. Chao-Lan Yu
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  2. Richard Jove
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  3. James Turkson
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Correspondence to James Turkson .

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  1. School of Medicine, Deakin University, Warun Ponds, Victoria, Australia

    Alister C. Ward

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Yu, CL., Jove, R., Turkson, J. (2016). Historical Development of STAT3 Inhibitors and Early Results in Clinical Trials. In: Ward, A. (eds) STAT Inhibitors in Cancer. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-42949-6_4

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