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
  • 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.
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