ZSTK3744

ZSTK3744 is an aromatic hydrocarbon receptor (AhR) agonist. It directly binds to AhR, enhancing the expression of AhR target genes such as CYP1A1, CYP1B1, and TIPARP, and mediates growth inhibitory activity in triple-negative breast cancer cells. ZSTK3744 induces apoptosis in these cancer cells and exhibits antitumor activity, making it useful for studying chemotherapy-resistant triple-negative breast cancer.

ZSTK3744, at concentrations ranging from 0.1 to 1000 nM over 72 hours, effectively inhibits the growth of MDA-MB-468 triple negative breast cancer (TNBC) cells with an IC50 of 0.87 nM and also suppresses the growth of doxorubicin-resistant MDA-MB-468/AR TNBC cells with an IC50 of 0.92 nM, as well as paclitaxel-resistant MDA-MB-468/PR TNBC cells, where the IC50 is 23.54 nM. Additionally, in a time-dependent manner over 1 to 24 hours, ZSTK3744 upregulates the mRNA expression of CYP1A1 and TIPARP in MDA-MB-468 TNBC cells, with significant induction observed after 1 hour of treatment. Within 24 hours, ZSTK3744 induces apoptosis in MDA-MB-468 TNBC cells, with its growth-inhibitory activity partially mediated via a caspase-dependent apoptotic pathway. This compound also strongly inhibits MDA-MB-453 TNBC cell growth with an IC50 of 1.14 nM and DU4475 TNBC cell growth, where the IC50 is less than 0.50 nM. However, it does not significantly inhibit the growth of Hs578T TNBC cells, as indicated by an IC50 greater than 500 nM.

ZSTK3744, administered intravenously at doses of 2.5-10 mg/kg on days 0, 7, and 14, significantly inhibits tumor growth in a dose-dependent manner in a doxorubicin-resistant triple-negative breast cancer (TNBC) mouse xenograft model. Additionally, ZSTK3744 at 1-5 mg/kg, i.v., on days 0, 4, and 8, suppresses tumor growth in a parental TNBC mouse xenograft model.