STAT3 inhibitors(Zhejiang Chinese Medical University)

STAT3 hyperactivation in metastatic and therapy-resistant melanoma drives tumorigenesis and immunotherapy resistance by promoting tumor-stromal interactions, making its inhibition a crucial therapeutic strategy. Interestingly, synthetic STAT3 inhibitors could not manage to enter clinical trials due to their short half-lives, poor bioavailability and non-specific effects. Here, we have shown that Galiellalactone, a natural, irreversible STAT3 inhibitor, blocks IL-6 and WNT5A-mediated STAT3 Phosphorylation and migration in BRAF-inhibitor (BRAFi)-sensitive melanoma cells. Galiellalactone treatment leads to prolonged STAT3 inhibition, which obstructs both metastatic functions and secretome-mediated paracrine interactions in both BRAFi-sensitive and resistant melanoma cells, via the reduction of MCAM and N-cadherin protein expression. Altogether, our findings support that Galiellalactone is a potential inhibitor that could block the metastatic function of drug-resistant melanoma cells and also obstruct the possible paracrine activation of STAT3 conferred by stromal cells present in the tumor microenvironment.

Signal Transducer and Activator of Transcription 3 (STAT3) is a key mediator in Breast Cancer (BC) progression, contributing to tumor proliferation, metastasis, survival, and resistance to chemotherapy. Phosphorylation of STAT3 at tyrosine 705 promotes its dimerization and nuclear translocation, where it activates oncogenic transcriptional programs. Due to its central role in BC pathogenesis, STAT3 has emerged as a promising molecular target for therapeutic intervention. To synthesize, characterize, and evaluate the anticancer efficacy of synthetic and natural compounds with a focus on their ability to inhibit STAT3 phosphorylation, suppress breast cancer cell proliferation, and induce apoptosis and autophagy

A comprehensive literature review was conducted using databases such as PubMed, Scopus, Relemed, and ResearchGate. Relevant studies were identified that examined the synthesis, molecular mechanisms, and therapeutic potential of STAT3 inhibitors. Synthetic derivatives and phytochemicals were considered for their inhibitory effects on STAT3 activation and associated cellular outcomes in breast cancers.

Several synthetic and natural compounds demonstrated significant inhibitory effects on STAT3 phosphorylation, leading to reduced breast cancer cell proliferation, migration, and survival. These agents effectively induced apoptosis and, in some cases, autophagy, highlighting their multifaceted anti-tumor mechanisms and elucidating the potential of these compounds as lead candidates for further preclinical and clinical development

Targeting STAT3 can be a significant therapeutic strategy, as both synthetic and natural compounds capable of inhibiting STAT3 signaling have been shown in preclinical studies. These findings provide valuable insights for cancer biologists, molecular researchers, and clinicians to explore STAT3 inhibitors as potential breast cancer therapeutics.