Targeting TMPRSS2-ERG Fusion-Driven Prostate Cancer using Novel HBS-α-Helicomimics

Stapled alpha-helicomimics designed to mimic the ERG recognition helix block ERG-DNA binding and suppress TMPRSS2-ERG fusion-driven prostate cancer, which occurs in roughly 50% of prostate cancers. The lead compound, stabilized by an N-terminal hydrogen-bond-surrogate macrocycle plus D363E and S366E mutations and dual NLS-TAT tags, inhibited ERG binding to ETS motifs, cut proliferation, migration and invasion in ERG-positive PCa cells, and suppressed tumor growth with reduced Ki-67 in a murine xenograft model without overt toxicity.