Research progress of STAT3-based dual inhibitors for cancer therapy.

Signal transducer and activator of transcription 3 (STAT3), a transcription factor, regulates gene levels that are associated with cell survival, cell cycle, and immune reaction. It is correlated with the grade of malignancy and the development of various cancers and targeting STAT3 protein is a potentially promising therapeutic strategy for tumors. Over the past 20 years, various compounds have been found to directly inhibit STAT3 activity via different strategies. However, numerous difficulties exist in the development of STAT3 inhibitors, such as serious toxic effects, poor therapeutic effects, and intrinsic and acquired drug resistance. STAT3 inhibitors synergistically suppress cancer development with additional anti-tumor drugs, such as indoleamine 2,3-dioxygenase 1 inhibitors (IDO1i), histone deacetylase inhibitors (HDACi), DNA inhibitors, pro-tumorigenic cytokine inhibitors (PTCi), NF-κB inhibitors, and tubulin inhibitors. Therefore, individual molecule- based dual-target inhibitors can be the candidate alternative or complementary treatment to overcome the disadvantages of just STAT3 or other targets as a monotherapy. In this review, we discuss the theoretical basis for formulating STAT3-based dual-target inhibitors and also summarize their structure-activity relationships (SARs).