An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects

    Authors

    K. A. Z. Siddiquee; P. T. Gunning; M. Glenn; W. P. Katt; S. Zhang; C. Schroeck; S. M. Sebti; R. Jove; A. D. Hamilton;J. Turkson

    Comments

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    Abbreviated Journal Title

    ACS Chem. Biol.

    Keywords

    UBIQUITIN-PROTEASOME SYSTEM; HUMAN PANCREATIC-CANCER; BREAST-CARCINOMA; CELLS; DNA-BINDING ACTIVITY; CONSTITUTIVE ACTIVATION; SIGNAL TRANSDUCER; GENE-REGULATION; AGGRESOME FORMATION; SRC ONCOPROTEIN; DRUG DISCOVERY; Biochemistry & Molecular Biology

    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-N12001, 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 nonfunctional 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 processing following inhibition by a small molecule that has significant antitumor activity.

    Journal Title

    Acs Chemical Biology

    Volume

    2

    Issue/Number

    12

    Publication Date

    1-1-2007

    Document Type

    Article

    Language

    English

    First Page

    787

    Last Page

    798

    WOS Identifier

    WOS:000251905100014

    ISSN

    1554-8929

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