Discovery of a Novel Dual-Targeting KRAS ^G12D /HDAC Peptide Inhibitor for the Treatment of Pancreatic Cancer

Pancreatic cancer (PC) remains a highly lethal malignant tumor with limited effective treatment options. Histone deacetylase (HDAC) serves as a downstream signal of the Kirsten rat sarcoma (KRAS) signaling pathway in PC cells. In this study, we innovatively identified the first peptide inhibitor (KH-1) that simultaneously inhibited KRAS^G12D and HDAC through integrated virtual screening strategies based on pharmacophore screening and molecular docking. Microscale thermophoresis (MST) assays validated the nanomolar binding affinity of KH-1 for KRAS^G12D (<i>K</i>_d = 11.63 ± 0.71 nM) and HDAC2 (<i>K</i>_d = 20.17 ± 1.26 nM). KH-1 significantly inhibited human pancreatic cell proliferation, invasion, and migration. Flow cytometry showed that KH-1 significantly induced cell apoptosis and cell cycle arrest at the G0/G1 phase. In addition, KH-1 exerted obvious tumor growth inhibition in a xenograft model without significant organ toxicity. Overall, this work identifies KH-1 as a highly promising dual-targeting KRAS^G12D/HDAC peptide inhibitor for pancreatic cancer therapy.