Helical Peptidomimetic Inhibitors Targeting the Histone Chaperone ASF1 for Cancer Therapy

Targeting protein-protein interactions (PPIs) with shallow, extended interfaces remains challenging, as exemplified by the histone chaperone ASF1. Here, we report de novo designed d-sulfonyl-γ-AApeptide foldamers that mimic the hot-spot residues of the histone H3 C-terminal α-helix that are essential for ASF1 recognition. The lead compound ASF-015 shows high-affinity binding to ASF1A and potent antiproliferative activity across cancer cell lines. These foldamers, completely resistant to proteolytic degradation, penetrate cells without a cell-penetrating peptide, engage intracellular ASF1, disrupt the ASF1-histone H3-H4 complex, and transcriptionally suppress proliferation and promote apoptosis. In the 4T1 and CT26 murine models, systemically administered ASF-015 inhibits tumor growth without detectable toxicity. This study establishes d-sulfonyl-γ-AApeptides as the first ASF1 inhibitors that simultaneously achieve high affinity, metabolic stability, autonomous permeability, and in vivo anti-tumor efficacy, offering a new strategy for targeting the ASF1-histone interface and other challenging PPIs in epigenetic drug discovery.