1204213-09-1Relevant articles and documents
Identification of a new series of STAT3 inhibitors by virtual screening
Matsuno, Kenji,Masuda, Yoshiaki,Uehara, Yutaka,Sato, Hiroshi,Muroya, Ayumu,Takahashi, Osamu,Yokotagawa, Takane,Furuya, Toshio,Okawara, Tadashi,Otsuka, Masami,Ogo, Naohisa,Ashizawa, Tadashi,Oshita, Chie,Tai, Sachiko,Ishii, Hidee,Akiyama, Yasuto,Asai, Akira
, p. 371 - 375 (2010)
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.
