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Identification of novel inhibitors of human equilibrative nucleoside transporter 4
Author(s) -
Wang Chunmei,
Buolamwini John
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.773.6
Subject(s) - nucleoside , chemistry , dipyridamole , transporter , nucleoside transporter , potency , quantitative structure–activity relationship , pharmacology , uridine , ic50 , structure–activity relationship , stereochemistry , biochemistry , in vitro , biology , medicine , gene , rna
To investigate the interaction of human nucleoside transporter 4 (hENT4) with dipyridamole analogues for the identification of novel needed potent and selective inhibitors. hENT4 was cloned and stably expressed in PK15NTD cells. A series of dipyridamole analogues synthesized in our laboratory were tested in this newly established hENT4 expressing system as inhibitors of [ 3 H]uridine uptake.. Comparative molecular field analyses three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) modeling was used to rationalize activity and selectivity. Of 73 dipyridamole analogues evaluated, 50 compounds were found to inhibit hENT4 with moderate to high potency (≥30%). About one fourth of compounds inhibited hENT4 with higher potencies than dipyridamole. The most potent compound (WL‐30) displayed an IC 50 of 74.4 nM, making it about 38 times more potent than dipyridamole (IC 50 = 2.8 μM). The structure‐activity relationships and insights gained into structural determinants of transporter inhibitory potency and selectivity relative to hENT1 and hENT2, by means of 3D‐QSAR modeling of will be presented. The hENT4 inhibitors identified in this study are novel and the most potent inhibitors reported to date, and should serve as useful pharmacological/biochemical tools and/or potential leads for ENT4‐based therapeutics. Supported by NIH grants CA125850, AI065372 and HL095002.