title: Discovery of the catechol structural moiety as a Stat3 SH2 domain inhibitor by virtual screening.
abstract: 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.
authors.affiliation: Oncology, Wyeth Pharmaceuticals, 401 N. Middletown Road, Pearl River, NY 10965, USA. haow@wyeth.com
authors.forename: Wenshan
authors.initials: W
authors.lastname: Hao
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Hu
authors.forename: Chuansheng
authors.initials: C
authors.lastname: Niu
authors.forename: Xinyi
authors.initials: X
authors.lastname: Huang
authors.forename: Chao-Pei Betty
authors.initials: CP
authors.lastname: Chang
authors.forename: James
authors.initials: J
authors.lastname: Gibbons
authors.forename: Jun
authors.initials: J
authors.lastname: Xu