Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.