STAT3/CAIX-IN-1 is a dual-target inhibitor of STAT3 (Kd: 60.03 μM) and CAIX (IC50: 80.45 nM). It induces ferroptosis by elevating reactive oxygen species (ROS) and lipid peroxides. This compound also inhibits cell migration, induces apoptosis, and causes cell cycle arrest in MDA-MB-231 cells. STAT3/CAIX-IN-1 is applicable for research in triple-negative breast cancer (TNBC).

CA IX:80.45 nM

STAT3/CAIX-IN-1 (Compound 7m) effectively inhibits the phosphorylation of STAT3 in MDA-MB-231 cells at concentrations of 2-8 μM over 24 hours. At 4 μM, it binds to STAT3, enhancing its stability. This compound enhances the proliferation inhibition of tumor cell lines with an IC50 of 2.18 μM under hypoxia and 4.21 μM under normoxia in MDA-MB-231 cells. Moreover, STAT3/CAIX-IN-1 induces ferroptosis via the GPX4 pathway, elevates reactive oxygen species levels, and increases lipid peroxidation in MDA-MB-231 cells at 4 μM and 8 μM over 24 hours. It also suppresses cell migration at 2 μM and 4 μM for 24-48 hours. At 4 μM and 8 μM for 24 hours, the compound induces apoptosis and causes G1/S phase cell cycle arrest in MDA-MB-231 cells. STAT3/CAIX-IN-1 demonstrates antitumor activity with IC50 values of 4.21 μM in MDA-MB-231 cells, 5.67 μM in MCF-7, 6.60 μM in MDA-MB-231/ADR, and 14.19 μM in MCF-10A.

STAT3/CAIX-IN-1 (Compound 7m) demonstrated antitumor activity at doses of 5 mg/kg and 10 mg/kg over 48 hours, achieving a response rate of 75% without affecting weight or behavior. When administered intraperitoneally at 10 mg/kg every other day for 21 days, it reduced phosphorylated STAT3 expression in Balb/c nude mice xenografts. Additionally, STAT3/CAIX-IN-1, at 5 mg/kg and 10 mg/kg intraperitoneally every other day for 21 days, inhibited tumor growth in Balb/c nude mice with MDA-MB-231 xenografts.