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  3. An NTCP-mediated liver-targeting chimeras (NTLiverTac) design strategy and its application to hepatoblastoma models

An NTCP-mediated liver-targeting chimeras (NTLiverTac) design strategy and its application to hepatoblastoma models

  • Bioorg Chem. 2025 Jul 15:162:108622. doi: 10.1016/j.bioorg.2025.108622.
Jing Liang 1,  Weihong Luo 2,  Wen Xu 2,  Siting Song 2,  Yutong Li 1,  Yang Liu 3,  Hua Li 4,  Lixia Chen 5
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
  • 3 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: spu_liuy@163.com.
  • 4 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. Electronic address: lihua@fjtcm.edu.cn.
  • 5 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: syzyclx@163.com.
PMID: 40424783 DOI: 10.1016/j.bioorg.2025.108622
Abstract

Hepatoblastoma (HB) has attracted much attention due to its high recurrence rate, and its first- and second-line chemotherapeutic agents have severe neurotoxicity, cardiotoxicity, and hepatorenal dysfunction. To enhance the liver-targeting efficiency, we proposed an NTCP-mediated liver-targeting chimeras (NTLiverTac) design strategy, which utilized the PROTAC molecule to couple with the Na+-taurocholate co-transporting polypeptide (NTCP) ligand to enhance cell selectivity through NTCP-mediated endocytosis. As a proof-of-concept, we selected cholic acid as its ligand, conjugated it with sorafenib and E3 Ligase ligand, and synthesized 25 NTLiverTacs through two generations of optimization. We evaluated the anti-proliferation activity and PDE6D degradation efficiency of NTLiverTacs in HuH-6 cells, a human HB cell line that was characterized by NTCP high expression. Among them, S2C2M2 showed an obvious anti-proliferative effect with the IC50 value of 7.46 ± 0.70 μM in HuH-6 cells and could effectively induce phosphodiesterase 6D (PDE6D) degradation in proteasome-dependent and NTCP-dependent manner. Mechanism research revealed that S2C2M2 effectively inhibited the PDE6D-dependent KRAS trafficking, modulated KRAS distribution and activity, and inhibited the oncogenic signaling cascade associated with KRAS. Our work demonstrated the practicality and efficiency of the NTLiverTac strategy and offered a promising avenue for degraders targeting Other pathogenic proteins relevant to HB.

Keywords

Hepatoblastoma; KRAS; NTCP; PDE6D degradation.

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