Discovery of 1,3-disubstituted indole derivatives as ATP-competitive inhibitors of sphingosine kinase for tumor therapy

  • Eur J Med Chem. 2026 May 22:316:118983. doi: 10.1016/j.ejmech.2026.118983.
Meiyan Zhang  1 ,  Yidan Huo  2 ,  Yali Song  3 ,  Longfei Li  3 ,  Ming Meng  4 ,  Jianshuang Guo  5 ,  Fei Cao  6 ,  Kan Yang  7
Affiliations
  • 1. Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China.
  • 2. Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China; Pharmacy Department, Baoding NO.1 Central Hospital, Baoding, Hebei, 071002, China.
  • 3. Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China.
  • 4. Medical School of Hebei University and Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, Hebei, 071002, China.
  • 5. Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China. Electronic address: [email protected].
  • 6. Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China. Electronic address: [email protected].
  • 7. Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China. Electronic address: [email protected].
PMID: 42229235 DOI: 10.1016/j.ejmech.2026.118983
Abstract

Targeting Sphingosine kinase (SphK1/2) has become a novel strategy for the treatment of Cancer. However, potent ATP competitive inhibitors are rare. Herein, a series of novel SphK1 and SphK2 inhibitors were identified through virtual screening and structural optimization. The structure-activity relationship revealed compound 9d had excellent inhibitory activity and selectivity on SphK1. 9d can increase the level of Sph while reducing the content of S1P in vivo and in vitro. Moreover, 9d demonstrated anti-tumor effect on various cell lines and mouse models. In addition, another compound 6a was found to have good inhibitory activity and selectivity on SphK2 and showed potent anti-proliferative activity on tumor cells. It can be studied as an inhibitor of SphK2 in the future.

Keywords
ATP competitive; Anti-tumor; Inhibitors; Sphingosine kinase.
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