Discovery of Carbohydrate Sulfotransferase Inhibitors from a Kinase-Directed Library We thank Sharon Long and Dave Keating for providing both the NodH sulfotransferase and APS Kinase during our preliminary experiments and Jack Kirsch for numerous helpful conversations. J.I.A. and K.G.B were supported by NIH Molecular Biophysics Training Grant (No. T32GM0895). This research was funded by grants to C.R.B. from the Pew Scholars Program, the W. M. Keck Foundation and the American Cancer Society (Grant No. RPG9700501BE).

Carbohydrate sulfotransferases have recently emerged as an important and relatively unexplored class of therapeutic targets.[1] For example, the seminal discovery that sulfated sialyl LewisX mediates the adhesion of leukocytes to inflamed endothelium established carbohydrate sulfotransferases as potential targets for anti-inflammatory therapy.[2] Ongoing genome sequencing projects have uncovered numerous carbohydrate sulfotransferase genes in the past few years.[1, 3] It is now apparent that carbohydrate sulfotransferases comprise a large family of enzymes with overlapping tissue distribution and substrate specificities. To deconvolute the precise role of each sulfotransferase gene product and elucidate its contribution to normal and pathological processes, cell-permeable and highly specific small-molecule antagonists need to be identified. Surprisingly, no inhibitor of a carbohydrate sulfotransferase has been reported to date. At present, the limited structural and mechanistic information about this class of enzymes impedes rational approaches to inhibitor design. To identify lead inhibitors of carbohydrate sulfotransferases, we therefore adopted a strategy that involved the screening of small-molecule libraries. To narrow our search, we focused on the similarities between the substrates utilized by sulfotransferases and kinases, a widely studied family of enzymes for which diverse and potent inhibitors are available.[4] Carbohydrate sulfotransferases catalyze the transfer of a sulfonyl group from the universal sulfate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to a hydroxy (or amino) group of the acceptor oligosaccharide (Scheme 1).