Bisphosphonate inhibitors of mammalian glycolytic aldolase.
JOURNAL OF MEDICINAL CHEMISTRY(2018)
摘要
The glycolytic enzyme aldolase is an emerging drug target in diseases such as cancer and protozoan infections which are dependent on a hyperglycolytic phenotype to synthesize adenosine 5'-triphosphate and metabolic precursors for biomass production. To date, structural information for the enzyme in complex with phosphate-derived inhibitors has been lacking. Thus, we determined the crystal structure of mammalian aldolase in complex with naphthalene 2,6-bisphosphate (1) that served as a template for the design of bisphosphonate-based inhibitors, namely, 2-phosphate-naphthalene 6-bisphosphonate (2), 2-naphthol 6-bisphosphonate (3), and 1-phosphate-benzene 4-bisphosphonate (4). All inhibitors targeted the active site, and the most promising lead, 2, exhibited slow-binding inhibition with an overall inhibition constant of, similar to 38 nM. Compound 2 inhibited proliferation of HeLa cancer cells, whereas HEK293 cells expressing a normal phenotype were not inhibited. The crystal structures delineated the essential features of high-affinity phosphate-derived inhibitors and provide a template for the development of inhibitors with prophylaxis potential.
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