Stat3 inhibitor having anti-cancer activity and methods
Inventors
Turkson, James • Sebti, Said • Jove, Richard • Hamilton, Andrew D.
Assignees
Yale University • University of South Florida • University of South Florida St Petersburg • University of Central Florida Research Foundation Inc
Publication Number
US-8609639-B2
Publication Date
2013-12-17
Expiration Date
2027-12-05
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Abstract
A small-molecule Stat3 dimerization inhibitor, S3I-M2001, is described and the dynamics of intracellular processing of activated Stat3 within the context of the biochemical and biological effects of the Stat3 chemical probe inhibitor are elucidated. S3I-M2001 is a newly-identified oxazole-based peptidomimetic of the Stat3 Src Homology (SH) 2 domain-binding phosphotyrosine peptide that selectively disrupts active Stat3:Stat3 dimers. Stat3-dependent malignant transformation, survival, and migration and invasion of mouse and human cancer cells harboring persistently-activated Stat3 were inhibited by S3I-M2001. S3I-M2001 inhibited Stat3-dependent transcriptional regulation of tumor survival genes, such as Bcl-xL. The disclosed compound is useful as a new potential treatment for certain cancers.
Core Innovation
The invention relates to a novel small-molecule inhibitor, S3I-M2001, designed to selectively disrupt Stat3:Stat3 dimerization and inhibit Stat3 activation. S3I-M2001 is described as an oxazole-based peptidomimetic that mimics the Stat3 Src Homology (SH) 2 domain-binding phosphotyrosine peptide, and specifically intervenes in the dimerization process necessary for Stat3 activity. The compound’s structure supports binding to the Stat3 SH2 domain with key hydrophobic and hydrophilic interactions, providing potent inhibition of Stat3 function and DNA binding.
The problem addressed by this invention is that constitutively-active Stat3 is implicated in the malignant transformation, survival, and progression of various human and mouse cancer cells. Existing research showed that disrupting Stat3 activation or dimerization induces cancer cell death and tumor regression; however, molecular details on Stat3 regulation and its processing after inhibition remained undefined. The invention aims to provide a selective small-molecule inhibitor that can serve both as a therapeutic agent against Stat3-dependent cancers and as a tool for probing intracellular Stat3 dynamics.
The compound S3I-M2001 was shown to inhibit Stat3-dependent transcription of tumor survival genes, such as Bcl-xL, block cancer cell viability, and inhibit growth and invasion of tumor cells harboring constitutively-active Stat3, including human breast and pancreatic cancer cells. Functional studies demonstrated that S3I-M2001 treatment leads to early aggregation of activated Stat3 into perinuclear aggresomes and subsequent proteasome-mediated degradation, effectively terminating Stat3 signaling in malignant cells. The invention includes pharmaceutical compositions containing S3I-M2001, methods for treating cancers with aberrant Stat3 activity, and approaches to inhibit tumor progression and malignant cell migration using this compound.
Claims Coverage
The patent contains multiple independent claims focused on the structure, composition, and methods of using S3I-M2001 to inhibit Stat3, along with applications in cancer treatment.
Oxazole-based Stat3 inhibitor compound (S3I-M2001)
A compound, or a pharmaceutically acceptable salt thereof, having a specific structure represented by a formula (as shown in the patent), which is an oxazole-based peptidomimetic designed to interact with the Stat3 SH2 domain.
Pharmaceutically acceptable composition containing S3I-M2001
A pharmaceutically acceptable composition containing S3I-M2001 or its salt, intended to be compatible with mammalian physiology for therapeutic use.
Composition for inhibiting Stat3 dimerization
A pharmaceutically acceptable composition containing S3I-M2001 in an effective amount to inhibit Stat3 dimerization in a mammalian cell upon contact.
Method of treating mammalian cells having dysfunctional Stat3
A method comprising contacting a mammalian cell with dysfunctional Stat3 with S3I-M2001 (or a composition containing S3I-M2001) to treat the cell.
Method of inhibiting constitutively active Stat3 in mammalian cells
A method comprising contacting a mammalian cell harboring constitutively active Stat3 with an effective amount of S3I-M2001 (or a composition containing S3I-M2001) to inhibit Stat3 activity.
Method of treating specific cancers characterized by constitutively active Stat3
A method of treating human breast or pancreatic cancer cells having a constitutively active level of Stat3 by administering a sufficient amount of S3I-M2001 (or a composition containing it) to the cancer cells.
Method for inhibiting growth or migration of cancer or malignant cells
A method for inhibiting growth of a human breast or pancreatic cancer tumor cell, or for inhibiting migration of a malignant cell, through contacting with S3I-M2001 or a pharmaceutical composition thereof.
The inventive features focus on a novel oxazole-based Stat3 inhibitor compound (S3I-M2001), related pharmaceutical compositions, and varied methods for treating Stat3-dysregulated cells and cancers, particularly those reliant on constitutively active Stat3.
Stated Advantages
S3I-M2001 selectively disrupts Stat3:Stat3 dimerization and inhibits Stat3 activation without significantly affecting other proteins such as Stat1 or unrelated SH2 domain proteins.
The compound demonstrates preferential inhibition of Stat3-dependent malignant transformation, survival, migration, and invasion in cancer cells, leading to selective antitumor effects.
S3I-M2001 provides a unique tool to probe intracellular Stat3 processing, revealing both early reversible aggresome formation and late irreversible proteasome-mediated degradation.
Effective reduction of Stat3-dependent transcription, including genes important for tumor survival (such as Bcl-xL), contributes to apoptosis and tumor regression.
Administration of S3I-M2001 inhibits the growth of human breast and pancreatic cancer xenografts in animal models, with treated animals remaining viable at effective doses.
Documented Applications
Treatment of mammalian cells, including human breast and pancreatic cancer cells, that exhibit constitutively active Stat3 by administering S3I-M2001 or its pharmaceutical compositions.
Inhibition of Stat3-dependent transcription, malignant transformation, cell survival, migration, and invasion in Stat3-activated cancer cells using S3I-M2001.
Use of S3I-M2001 as a chemical probe to study Stat3 intracellular processing, dimerization, and degradation mechanisms in malignant cells.
Inhibition of tumor growth in vivo, demonstrated in human breast cancer xenograft models by administering S3I-M2001.
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