Document Report Card

ID: ALA1687687

Journal: ACS Med Chem Lett

Title: Identification of a New Series of STAT3 Inhibitors by Virtual Screening.

Authors: Matsuno K, Masuda Y, Uehara Y, Sato H, Muroya A, Takahashi O, Yokotagawa T, Furuya T, Okawara T, Otsuka M, Ogo N, Ashizawa T, Oshita C, Tai S, Ishii H, Akiyama Y, Asai A.

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.

CiteXplore: 24900220

DOI: 10.1021/ml1000273