STAT3-IN-51 is a STAT3 inhibitor that binds directly to the SH2 domain of STAT3. This compound induces apoptosis, ferroptosis, and immunogenic cell death (ICD), enhancing antitumor immunity. It suppresses STAT3 activation (phosphorylation, p-STAT3) and its downstream signaling, while prompting reactive oxygen species (ROS) generation, decreasing Bcl-2 expression, disrupting mitochondrial functions, inhibiting GPX4 activity, and promoting lipid peroxidation. STAT3-IN-51 is applicable in research on colorectal cancer, breast adenocarcinoma, non-small cell lung cancer (NSCLC), and cisplatin-resistant lung adenocarcinoma.

STAT3-IN-51 (Compound 8d) demonstrates significant antiproliferative activity against SW480, MDA-MB-231, A549, and A549/DDP cancer cell lines, with IC50 values of 0.26 μM, 0.34 μM, 0.61 μM, and 0.67 μM respectively. At a concentration of 0.3 μM for 24 hours, STAT3-IN-51 induces apoptosis in SW480 cells through mitochondrial dysfunction and caspase activation, effectively inhibits total and phosphorylated STAT3 in these cells, promotes CD8+ T lymphocyte infiltration and proliferation, facilitates dendritic cell maturation, reduces HMGB1 levels, and triggers ferroptosis in SW480 cells via GPX4 inhibition and lipid peroxidation.

STAT3-IN-51 (Compound 8d) administered via intraperitoneal injection every other day at doses of 5-10 mg/kg for 13 days significantly inhibited tumor growth in the CT26 xenograft model and demonstrated good safety.