Hijacking the Hydrogen Sulfide Axis: A Novel 4-Trifluoromethylquinoline Derivative Suppresses Glioblastoma via Cystathionine γ-Lyase Suppression

  • J Med Chem. 2026 Feb 12;69(3):3457-3476. doi: 10.1021/acs.jmedchem.5c03477.
Zhiqiong Luo  1  2 ,  Guangcan Xu  2  3 ,  Cheng Li  3 ,  Zhilu Sun  4 ,  Haonan Chen  1  2 ,  Mingyue Yang  2 ,  Yi Ye  2  4 ,  Qianyu Chen  1 ,  Bixue Xu  2  3 ,  Heng Luo  1  2  3 ,  Baofei Sun  1  2
Affiliations
  • 1. Key Laboratory of Human Brain Bank for Functions and Diseases, Department of Education of Guizhou Province, College of Basic Medical, Guizhou Medical University, Guiyang 561113, China.
  • 2. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang 550014, China.
  • 3. Natural Products Research Center of Guizhou Province, Guiyang 550016, China.
  • 4. Clinical Medicine College, Guizhou Medical University, Guiyang 550004, China.
PMID: 41632838 DOI: 10.1021/acs.jmedchem.5c03477
Abstract

Cystathionine γ-lyase (CTH) is markedly enriched in glioblastoma (GBM) and is associated with poor patient survival, enhanced temozolomide (TMZ) resistance, and aggressive phenotypes; however, effective CTH inhibitors for GBM therapy are currently lacking. Using click chemistry-based target identification, we identified cystathionine γ-lyase (CTH) as the direct molecular target of a novel 4-trifluoromethylquinoline derivative, TKL002. TKL002 exhibits strong antitumor activity both in vitro and in vivo, inducing late-stage Apoptosis and G2/M cell cycle arrest. Mechanistically, TKL002 inhibits CTH activity, reduces hydrogen sulfide (H2S) production, suppresses NF-κB phosphorylation, and downregulates pro-inflammatory cytokine expression. In addition, TKL002 inhibits GBM cell migration and invasion by upregulating E-cadherin and downregulating N-Cadherin and vimentin. Collectively, these findings demonstrate that TKL002 exerts potent antiglioblastoma activity via modulation of the CTH/H2S/NF-κB/EMT signaling axis, highlighting its potential as a quinoline-based therapeutic candidate to overcome intrinsic GBM resistance and invasiveness.

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