Revisiting the development of small molecular inhibitors that directly target the signal transducer and activator of transcription 3 (STAT3) domains.

Signal transducer and activator of transcription 3 (STAT3) has been a protein target following its roles being found to play in the progression of cancer development, cancer stemness, chemoresistance and radioresistance. Two decades of research efforts in STAT3 has, however, not yielded a marketed anti-STAT3 drug. This review insightfully discusses structural views on the STAT3 domains (e.g. binding pockets and critical residues), approaches to discovering effective chemical structures (e.g. structure-based drug discovery, high-throughput screening, natural product derivatives, repurposing drugs and so on), how the domains were targeted (e.g. non-covalent or covalent inhibition), and rationale of domain targeting (e.g. prevention of homo-dimerization or DNA-binding). In addition, the assays that have been used for the discovery of STAT3 inhibitors will be discussed. Overall, with this review article, the progress of the development of STAT3 antagonists could be accelerated.