期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 18, 期 18, 页码 4988-4992出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.08.032
关键词
virtual screening; catechol; Stat3; SH2; inhibitors
The Stat3 SH2 domain is essential for its activation, and development of a potent SH2 inhibitor will be therapeutically valuable in treating cancers with constant Stat3 activation. We report here the identification of the catechol (1,2-dihydroxybenzene) structural moiety by virtual screening as a Stat3 SH2 inhibitor. The catechol compound docked to the Stat3 SH2 domain in computer modeling forms hydrogen bonds with the conserved pTyr-interacting amino acids. In the biochemical assay, a catechol-containing compound, but not the hydroxyl group-acetalized analogue, was able to inhibit Stat3 DNA-binding activity. Furthermore, the catechol compound was demonstrated to compete with pTyr peptides in binding to the Stat3 SH2 domain, suggesting that the catechol moiety is a pTyr bioisostere and may potentially be used for designing cell-permeable SH2 inhibitors. In our preliminary effort, we also demonstrated that the potency of catechol compound as Stat3 SH2 inhibitors could be improved by modifying the non-catechol part of the compound structure. (C) 2008 Elsevier Ltd. All rights reserved.
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