Design, Synthesis, and Evaluation of Bibenzyl Analogues against Hepatocellular Carcinoma by Targeting Pyruvate Carboxylase

  • J Med Chem. 2026 Jun 25;69(12):14333-14364. doi: 10.1021/acs.jmedchem.6c00075.
Zeen Qiao  1  2 ,  Lingyu Li  1  2 ,  Yuwen Sheng  1 ,  Jinlian Yang  1  2 ,  Jialing Yu  1  2 ,  Fan Wu  1  2 ,  Minghui Ji  1  2 ,  Ruiying Xi  1 ,  Linhan Yang  1  2 ,  Guolin Zhang  1 ,  Xiaoxia Lu  1 ,  Xiaofeng Ma  1 ,  Fei Wang  1
Affiliations
  • 1. National Engineering Research Center for Natural Medicines, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610213, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 42286802 DOI: 10.1021/acs.jmedchem.6c00075
Abstract

Pyruvate carboxylase (PC) replenishes tricarboxylic acid cycle intermediates, driving Cancer metabolic reprogramming. To improve the metabolic stability of erianin, a potent PC inhibitor from Dendrobium chrysotoxum Lindl, we designed and synthesized 55 derivatives, culminating in the identification of CIB-Q22, which exhibited potent PC inhibition (IC50 = 1.74 nM) and suppressed HCC cell viability (IC50 = 25.18 nM), comparable to erianin. Notably, CIB-Q22 demonstrated significantly improved in vivo stability, with a half-life (T1/2 = 1.21 h) much longer than erianin (T1/2 ∼ 0.1 h). Mechanistically, CIB-Q22 suppressed HCC proliferation and metastasis by inducing Apoptosis and Ferroptosis. Moreover, it promoted mitochondrial oxidative stress and inhibited glycolysis, thereby sensitizing cells to glutamine deprivation. In vivo, CIB-Q22 exhibited comparable antitumor efficacy but improved safety compared to sorafenib. With its potent PC inhibition and favorable drug-like properties, CIB-Q22 represented a promising therapeutic candidate for HCC treatment.

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