Discovery of a Novel Dual-Targeting KRASG12D/HDAC Peptide Inhibitor for the Treatment of Pancreatic Cancer

  • J Med Chem. 2026 Mar 12;69(5):5425-5440. doi: 10.1021/acs.jmedchem.5c02435.
Qiaoxuan Zhang  1 ,  Yifei Geng  2  3 ,  Haitao Chen  4 ,  Jiaping Ni  2  5 ,  Lixia Guan  2  3 ,  Dong Qing Zhai  2  5 ,  Yuting Wang  2  3 ,  Shengtao Xu  6 ,  Miao-Miao Niu  2  3 ,  Lufeng Zheng  4 ,  Weiwei Hu  2  5
Affiliations
  • 1. Department of Laboratory Medicine/State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China.
  • 2. Institute of Translational Medicine, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 211198, China.
  • 4. School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 211198, China.
  • 5. School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 6. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41736662 DOI: 10.1021/acs.jmedchem.5c02435
Abstract

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 KRASG12D 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 KRASG12D (Kd = 11.63 ± 0.71 nM) and HDAC2 (Kd = 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 KRASG12D/HDAC peptide inhibitor for pancreatic Cancer therapy.

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