Discovery of novel NQO1/STAT3/HDAC triple-target agents for the treatment of triple negative breast cancer.

Simultaneous intervention of two or even multiple targets is an effective anticancer strategy owing to the complex mechanism behind tumorigenesis. In this study, a series of novel napabucasin-based NQO1/STAT3/HDAC triple-target agents were designed and synthesized, and their biological effects were assessed. Among them, SHN7 exerted the strongest inhibitory effect on the proliferation of triple negative breast cancer (TNBC) cells Hs578T, HCC1937, MDA-MB-231 and MDA-MB-468, with IC50 values of 0.16 ± 0.00 μM, 0.43 ± 0.08 μM, 0.58 ± 0.16 μM and 0.97 ± 0.09 μM, respectively. Moreover, SHN7 adequately inhibited HDAC1 (IC50 = 30 nM) and HDAC6 (IC50 = 10 nM), showed an excellent reduction rate by NQO1 (kcat/Km = 5.80 × 106 M-1 s-1), and bound to STAT3 with high binding affinity (KD = 8.9 μM). Mechanically, SHN7 suppressed the proliferation of Hs578T cells by promoting the acetylation of histone 3 (H3) and α-tubulin, downregulating the expression of p-STAT3, and increasing ROS production. Additionally, SHN7 arrested the cell cycle at the G2/M phase, prevented the migration of Hs578T cells, and promoted their apoptosis. Notably, SHN7 exerted strong in vivo anti-tumor effects relative to napabucasin and SAHA, with minimal toxic effects. Therefore, SHN7 may be a promising NQO1/STAT3/HDAC triple-target agent that can decrease the resistance of TNBC to HDAC inhibitors and can be developed as a candidate anti-TNBC drug.