title: Identification of a New Series of STAT3 Inhibitors by Virtual Screening.
abstract: The signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for oncology drug development. We identified a N-[2-(1,3,4-oxadiazolyl)]-4-quinolinecarboxamide derivative, STX-0119, as a novel STAT3 dimerization inhibitor by a virtual screen using a customized version of the DOCK4 program with the crystal structure of STAT3. In addition, we used in vitro cell-based assays such as the luciferase reporter gene assay and the fluorescence resonance energy transfer-based STAT3 dimerization assay. STX-0119 selectively abrogated the DNA binding activity of STAT3 and suppressed the expression of STAT3-regulated oncoproteins such as c-myc and survivin in cancer cells. In contrast, a truncated inactive analogue, STX-0872, did not exhibit those activities. Oral administration of STX-0119 effectively abrogated the growth of human lymphoma cells in a SCC-3 subcutaneous xenograft model without visible toxicity. Structure-activity relationships of STX-0119 derivatives were investigated using the docking model of the STAT3-SH2 domain/STX-0119.
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan ; PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Masuda
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.affiliation: PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Muroya
authors.affiliation: PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takahashi
authors.affiliation: PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan.
authors.forename: Takane
authors.initials: T
authors.lastname: Yokotagawa
authors.affiliation: PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Furuya
authors.affiliation: Kumamoto Health Science University, 325 Izumimachi, Kumamoto, 861-5598, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okawara
authors.affiliation: Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
authors.affiliation: Shizuoka Institute of Environment and Hygiene, 4-27-2 Kita-ando, Aoi-ku, Shizuoka, 420-8637, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Ogo
authors.affiliation: Shizuoka Cancer Center Research Institute, 1007 Shimo-nagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ashizawa
authors.affiliation: Shizuoka Cancer Center Research Institute, 1007 Shimo-nagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Oshita
authors.affiliation: Shizuoka Cancer Center Research Institute, 1007 Shimo-nagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tai
authors.affiliation: Shizuoka Cancer Center Research Institute, 1007 Shimo-nagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
authors.forename: Hidee
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Shizuoka Cancer Center Research Institute, 1007 Shimo-nagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
keywords: STAT3; antitumor; dimerization; inhibitor; protein−protein interaction; virtual screening