2. Academic Validation
  3. Binding and ubiquitination-mediated degradation of ACKR3 by the novel Scutellarein derivative TBS6b potently suppresses hepatocellular carcinoma

Binding and ubiquitination-mediated degradation of ACKR3 by the novel Scutellarein derivative TBS6b potently suppresses hepatocellular carcinoma

  • Bioorg Chem. 2025 Nov:166:109073. doi: 10.1016/j.bioorg.2025.109073.
Xing Jiang 1,  Ying Liang 2,  Guotao Tang 3,  Haiyan Quan 4,  Lijun Ruan 2,  Mengli Zhang 2,  Zhijun Song 2,  Min Ou 2,  Zhien Tan 2,  Na Lu 2,  Fangfang Wu 5,  Xiaonan Yang 6
Affiliations

Affiliations

  • 1 National Engineering Research Center for Southwest Endangered Medicinal Resources Development, Guangxi Key Laboratory of Medicinal Resources Protection and Genetic Improvement, Guangxi Botanical Garden of Medicinal Plants, Nanning, Guangxi 530023, PR China; Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, lnstitute of Pharmacy and Pharmacology, the Second Affiliated Hospital, University of South China, Hengyang, Hunan 421001, PR China.
  • 2 National Engineering Research Center for Southwest Endangered Medicinal Resources Development, Guangxi Key Laboratory of Medicinal Resources Protection and Genetic Improvement, Guangxi Botanical Garden of Medicinal Plants, Nanning, Guangxi 530023, PR China.
  • 3 Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China.
  • 4 Hunan Polytechnic of Environment and Biology, Hengyang, Hunan 421001, PR China.
  • 5 National Engineering Research Center for Southwest Endangered Medicinal Resources Development, Guangxi Key Laboratory of Medicinal Resources Protection and Genetic Improvement, Guangxi Botanical Garden of Medicinal Plants, Nanning, Guangxi 530023, PR China; Engineering Research Center of Innovative Traditional Chinese, Zhuang and Yao Materia Medica, Ministry of Education, Guangxi University of Chinese Medicine, Nanning, Guangxi 530001, PR China. Electronic address: [email protected].
  • 6 National Engineering Research Center for Southwest Endangered Medicinal Resources Development, Guangxi Key Laboratory of Medicinal Resources Protection and Genetic Improvement, Guangxi Botanical Garden of Medicinal Plants, Nanning, Guangxi 530023, PR China. Electronic address: [email protected].
PMID: 41075613 DOI: 10.1016/j.bioorg.2025.109073
Abstract

Scutellarein, a flavonoid compound from the traditional Chinese herb Scutellaria baicalensis, exhibits inhibitory effects against hepatocellular carcinoma (HCC), but its clinical application is limited by relatively weak potency. To enhance its antitumor activity, we synthesized a novel derivative, 5,6,7-trimethoxy-4'-benzimidazolyl scutellarein 6b (TBS6b), by introducing antitumor pharmacophores-trimethoxyphenyl and benzimidazole-into the scutellarein scaffold. TBS6b demonstrated significantly improved anti-HCC activity both in vitro and in vivo. Cell-based assays, including colony formation, EdU staining, wound healing, transwell migration, and western blot analysis, demonstrated that TBS6b significantly inhibits HCC cell proliferation, migration, and invasion. Mechanistically, we employed proteomic and transcriptomic Sequencing, along with western blot and qRT-PCR experiments, to predict and validate atypical Chemokine Receptor 3 (ACKR3) as the target of TBS6b. Molecular docking studies confirmed that TBS6b binds tightly to the ACKR3 protein. Additionally, with the aid of pharmacological tools, we established that TBS6b promotes the ubiquitination and degradation of ACKR3. Tissue microarray analysis and queries of public databases revealed that ACKR3 expression is elevated in HCC tissues compared to adjacent non-cancerous tissues, correlating closely with patient survival. By constructing cell lines with either silenced or overexpressed ACKR3, we confirmed that ACKR3 promotes the proliferation, migration, and invasion of HCC. Finally, rescue experiments indicated that TBS6b exerts its Anticancer effects primarily through targeting ACKR3. These findings establish ACKR3 as a critical target through which TBS6b mediates its Anticancer activity against HCC.

Keywords

ACKR3; Hepatocellular carcinoma; Invasion; Migration; Proliferation; Scutellarein derivative TBS6b; Ubiquitination.

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