2. Academic Validation
  3. A high-throughput screening campaign against PFKFB3 identified potential inhibitors with novel scaffolds

A high-throughput screening campaign against PFKFB3 identified potential inhibitors with novel scaffolds

  • Acta Pharmacol Sin. 2022 Sep 16. doi: 10.1038/s41401-022-00989-1.
Jie Li 1,  Yan Zhou 2,  Guy Eelen 3,  Qing-Tong Zhou 1,  Wen-Bo Feng 1,  Viktorija Labroska 2 4,  Fen-Fen Ma 5,  Hui-Ping Lu 5,  Mieke Dewerchin 3,  Peter Carmeliet 3,  Ming-Wei Wang 6 7 8 9 10,  De-Hua Yang 11 12 13
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • 2 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven and Center for Cancer Biology, VIB-KU Leuven, Leuven, 3000, Belgium.
  • 4 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5 Department of Pharmacy, Pudong Hospital, Fudan University, Shanghai, 201300, China.
  • 6 Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. mwwang@simm.ac.cn.
  • 7 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. mwwang@simm.ac.cn.
  • 8 University of Chinese Academy of Sciences, Beijing, 100049, China. mwwang@simm.ac.cn.
  • 9 Research Center for Deepsea Bioresources, Sanya, 572025, China. mwwang@simm.ac.cn.
  • 10 Department of Chemistry, School of Science, The University of Tokyo, Tokyo, 113-0033, Japan. mwwang@simm.ac.cn.
  • 11 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. dhyang@simm.ac.cn.
  • 12 University of Chinese Academy of Sciences, Beijing, 100049, China. dhyang@simm.ac.cn.
  • 13 Research Center for Deepsea Bioresources, Sanya, 572025, China. dhyang@simm.ac.cn.
PMID: 36114272 DOI: 10.1038/s41401-022-00989-1
Abstract

The growth of solid tumors depends on tumor vascularization and the endothelial cells (ECs) that line the lumen of blood vessels. ECs generate a large fraction of ATP through glycolysis, and elevation of their glycolytic activity is associated with angiogenic behavior in solid tumors. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) positively regulates glycolysis via fructose-2/6-bisphosphate, the product of its kinase activity. Partial inhibition of glycolysis in tumor ECs by targeting PFKFB3 normalizes the otherwise abnormal tumor vessels, thereby reducing metastasis and improving the outcome of chemotherapy. Although a limited number of tool compounds exist, orally available PFKFB3 inhibitors are unavailable. In this study we conducted a high-throughput screening campaign against the kinase activity of PFKFB3, involving 250,240 chemical compounds. A total of 507 initial hits showing >50% inhibition at 20 µM were identified, 66 of them plus 1 analog from a similarity search consistently displayed low IC50 values (<10 µM). In vitro experiments yielded 22 nontoxic hits that suppressed the tube formation of primary human umbilical vein ECs at 10 µM. Of them, 15 exhibited binding affinity to PFKFB3 in surface plasmon resonance assays, including 3 (WNN0403-E003, WNN1352-H007 and WNN1542-F004) that passed the pan-assay interference compounds screening without warning flags. This study provides potential leads to the development of new PFKFB3 inhibitors.

Keywords

PFKFB3 inhibitors; angiogenesis; glycolysis; high-throughput screening; solid tumors.

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