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Curr Med Chem. 2018 Jul 19. doi: 10.2174/0929867325666180719122729. [Epub ahead of print]

Signal Transducer and Activator of Transcription Protein 3 (STAT3): an Update on its Direct Inhibitors as Promising Anticancer Agents.

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Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Milano, via L. Mangiagalli 25, 20133 Milano. Italy.



Since Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor which plays an important role in multiple aspects of cancer, including progression and migration, and it is constitutively activated in various human tumors, STAT3 inhibition has emerged as a validated strategy for the treatment of several malignancies. The aim of this review is to provide an update on the identification of new promising direct inhibitors targeting STAT3 domains, as potential anticancer agents.


A thorough literature search focused on recently reported STAT3 direct inhibitors was undertaken. We considered the relevant developments regarding the STAT3 domains, which have been identified as potential drug targets.


In detail, 135 peer-reviewed papers and 7 patents were cited; the inhibitors we took into account targeted the DNA binding domain (compounds were grouped into natural derivatives, small molecules, peptides, aptamers and oligonucleotides), the SH2 binding domain (natural, semi-synthetic and synthetic compounds) and specific residues, like cysteines (natural, semi-synthetic, synthetic compounds and dual inhibitors) and tyrosine 705.


The huge number of direct STAT3 inhibitors recently identified demonstrates a strong interest in the investigation of this target, although it represents a challenging task considering that no drug targeting this enzyme is currently available for anticancer therapy. Notably, many studies on the available inhibitors evidenced that some of them possess a dual mechanism of action.


DNA binding domain.; SH2 domain; antitumor agents; signaling pathway; small molecules; transcription factor

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