2. Academic Validation
  3. Identification of a New Series of STAT3 Inhibitors by Virtual Screening

Identification of a New Series of STAT3 Inhibitors by Virtual Screening

  • ACS Med Chem Lett. 2010 Jul 13;1(8):371-5. doi: 10.1021/ml1000273.
Kenji Matsuno 1,  Yoshiaki Masuda 2,  Yutaka Uehara 1,  Hiroshi Sato 1,  Ayumu Muroya 3,  Osamu Takahashi 3,  Takane Yokotagawa 3,  Toshio Furuya 3,  Tadashi Okawara 4,  Masami Otsuka 5,  Naohisa Ogo 6,  Tadashi Ashizawa 7,  Chie Oshita 7,  Sachiko Tai 7,  Hidee Ishii 7,  Yasuto Akiyama 7,  Akira Asai 1
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
  • 2 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.
  • 3 PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan.
  • 4 Kumamoto Health Science University, 325 Izumimachi, Kumamoto, 861-5598, Japan.
  • 5 Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan.
  • 6 Shizuoka Institute of Environment and Hygiene, 4-27-2 Kita-ando, Aoi-ku, Shizuoka, 420-8637, Japan.
  • 7 Shizuoka Cancer Center Research Institute, 1007 Shimo-nagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
PMID: 24900220 DOI: 10.1021/ml1000273
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.

Keywords

STAT3; antitumor; dimerization; inhibitor; protein−protein interaction; virtual screening.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-103692
    99.21%, STAT3 Dimerization Inhibitor