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

Autor: Jie Li, Yan Zhou, Guy Eelen, Qing-tong Zhou, Wen-bo Feng, Viktorija Labroska, Fen-fen Ma, Hui-ping Lu, Mieke Dewerchin, Peter Carmeliet, Ming-wei Wang, De-hua Yang
Rok vydání: 2022
Předmět:
Zdroj: Acta pharmacologica Sinica.
ISSN: 1745-7254
Popis: 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 showing50% inhibition at 20 µM were identified, 66 of them plus 1 analog from a similarity search consistently displayed low IC
Databáze: OpenAIRE
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