S3I-M2001

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Description

S3I-M2001 is a novel small-molecule Stat3 inhibitor with IC50 of 79, 92 and 159 uM for Stat3:Stat3, Stat1:Stat3 and Stat1:Stat1, respectively. S3I-M2001 is designed to be an oxazole-based peptidomimetic of the Stat3 Src homology (SH) 2 domain-binding phosphotyrosine peptide that selectively disrupts active Stat3:Stat3 dimers. As a result, hyperactivated Stat3, which hitherto occurs as “dotlike” structures of nuclear bodies, undergoes an early aggregation into nonfunctional perinuclear aggresomes and a late-phase proteasome-mediated degradation in malignant cells treated with S3I-M2001. S3I-M2001 favorably disrupts Stat3 activity in vitro in nuclear extracts containing activated Stat3 or in lysates from Sf-9 cells containing activated Stat3, and preferentially inhibits Stat3 activity over Stat1 by 2-fold. Therefore, S3I-M2001 inhibited Stat3-dependent transcriptional regulation of tumor survival genes, such as Bcl-xL. Furthermore, S3I-M2001 prevented constitutive Stat3 Tyr phosphorylation and activation in the NIH3T3/v-Src and the human breast cancer MDA-MB-231 and MDA-MB-435 cell lines that harbor constitutively active Stat3. Stat3-dependent malignant transformation, survival, and migration and invasion of mouse and human cancer cells harboring persistently activated Stat3 were inhibited by S3I-M2001. In addition, S3I-M2001 prevented growth of human breast tumor xenografts.

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