Discovery of a Novel G‑Quadruplex and Histone Deacetylase (HDAC) Dual-Targeting Agent for the Treatment of Triple-Negative Breast Cancer

The development of triple-negative breast cancer (TNBC)
is highly
associated with G-quadruplex (G4); thus, targeting G4 is a potential
strategy for TNBC therapy. Because concomitant histone deacetylases
(HDAC) inhibition could amplify the impact of G4-targeting compounds,
we designed and synthesized two novel series of G4/HDAC dual-targeting
compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors
to the G4-targeting isaindigotone scaffold (1). Among
the new compounds, a6 with the potent HDAC inhibitory
and G4 stabilizing activity could induce more DNA G4 formation than
SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially
expressed genes, consistent with its effect on disrupting the cell
cycle, invasion, and glycolysis. Furthermore, a6 significantly
suppresses the proliferation of various TNBC cells and the MDA-MB-231
xenograft model without evident toxicity. Our study suggests a novel
strategy for TNBC therapeutics through dual-targeting HDAC and G4.