2. Academic Validation
  3. Identification of the target ANTXR1 and covalent acylation mechanism of 8-esterified cycloberberines against cancer

Identification of the target ANTXR1 and covalent acylation mechanism of 8-esterified cycloberberines against cancer

  • Eur J Med Chem. 2026 Oct 5:315:118965. doi: 10.1016/j.ejmech.2026.118965.
Jia Tang 1,  Xican Ma 1,  Xuelei Wang 1,  Guimin Xia 1,  Xintong Zhang 1,  Zhihui Yu 1,  Jingyang Zhu 1,  Xinyi Li 1,  Zhiyun Wu 1,  Runze Meng 1,  Yanan Ni 1,  Tianyun Fan 2,  Yinghong Li 3,  Danqing Song 4
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 42143941 DOI: 10.1016/j.ejmech.2026.118965
Abstract

An ester group can serve as a covalent warhead to acylate amino acid residues around the active cavity of the target protein, thereby silencing its biological function. In this study, taking 8-(benzoyloxy) cycloberberine (1) as the lead, twenty-seven 8-esterified cycloberberine (CBBR) derivatives were continuously synthesized and evaluated for their anti-tumor activities. Among them, compound 8a exhibited an appealing potency against a variety of tumor cells with IC50 values ranging 1.91-5.09 μM, significantly outperforming the lead 1. Cell cycle analysis showed 8a-induced G2/M phase arrest, which suggested ANTXR1 as a candidate target via thermal proteome profiling (TPP) assay. Further cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) analysis identified ANTXR1 as a direct target of 8a (KD = 2.88 μM). LC-MS/MS, molecule docking and molecular dynamics simulations (MD) demonstrated that the 8-adamantane acetyl in 8a could undergo an acylation reaction with Ser229 of ANTXR1, thereby inhibiting tumor cell proliferation. Therefore, compound 8a is a covalent inhibitor of ANTXR1, and introducing an ester group as the chemical warhead represents a highly effective structural modification strategy in medicinal chemistry.

Keywords

ANTXR1; Acylation covalent; Anti-tumor activity; Esterified cycloberberine; Synthesis.

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