An oxazole-based small-molecule stat3 inhibitor modulates stat3 stability and processing and induces antitumor cell effects

Khandaker A.Z. Siddiquee, Patrick T. Gunning, Matthew Glen, William P. Katt, Shumin Zhang, Christopher Schroeck, Said M. Sebti, Richard Jove, Andrew D. Hamilton, James Turkson

Research output: Contribution to journalArticle

Abstract

Stat3 is hyperactivated in many human tumors and represents a valid target for anticancer drug design. We present a novel small-molecule Stat3 inhibitor, S3I-M2001, and describe the dynamics of intracellular processing of activated Stat3 within the context of the biochemical and biological effects of the Stat3 inhibitor. S3I-M2001 is an oxazole-based peptidomimetic of the Stat3 Src homology (SH) 2 domain-binding phosphotyrosine peptide that selectively disrupts active Stat3:Stat3 dimers. Consequently, hyperactivated Stat3, which hitherto occurs as "dotlike" structures of nuclear bodies, undergoes an early aggregation into non-functional perinuclear aggresomes and a late-phase proteasome-mediated degradation in malignant cells treated with S3I-M2001. Thus, S3I-M2001 inhibited Stat3-dependent transcriptional regulation of tumor survival genes, such as Bcl-xL. Furthermore, Stat3-dependent malignant transformation, survival, and migration and invasion of mouse and human cancer cells harboring persistently activated Stat3 were inhibited by S3I-M2001. Finally, S3I-M2001 inhibited growth of human breast tumor xenografts. The study identifies a novel Stat3 Inhibitor, S3I-M2001, with antitumor cell effects mediated in part through a biphasic loss of functional Stat3. The study represents the first on intracellular Stat3 stability and procesing following inhibition by a small molecule that has significant antitumor activity.

Original languageEnglish (US)
Pages (from-to)787-798
Number of pages12
JournalACS Chemical Biology
Volume2
Issue number12
DOIs
StatePublished - Dec 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Siddiquee, K. A. Z., Gunning, P. T., Glen, M., Katt, W. P., Zhang, S., Schroeck, C., Sebti, S. M., Jove, R., Hamilton, A. D., & Turkson, J. (2007). An oxazole-based small-molecule stat3 inhibitor modulates stat3 stability and processing and induces antitumor cell effects. ACS Chemical Biology, 2(12), 787-798. https://doi.org/10.1021/cb7001973