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Background
The signal transducers and activators of transcription (STATs) are a class of transcription factor proteins that regulate cell growth and survival. A total of seven STAT isoforms, encoded in distinct genes, have been identified in mammalian cells. Stat3 protein isoform is known to directly up-regulate Bcl-xL, Mcl-1, cyclin D1/D2 and c-myc, contributing to compromised regulation by stimulating cell proliferation and preventing apoptosis in numerous human cancers. Stat3 activation occurs via phosphorylation of tyrosine 705, which promotes STAT dimer formation through STAT phosphotyrosine-SH2 domain interactions. These STAT dimers translocate to the nucleus, where they regulate gene expression. Constitutive Stat3 activity mediates dysregulated growth and survival, angiogenesis, as well as suppresses the host's immune surveillance of tumors and represents a valid target for small molecule anti-cancer design.
Invention
A novel oxazole-based peptidomimetic, designated S3I-M2001, was synthesized and shown to be a selective disruptor of Stat3:Stat3 dimerization and inhibitor of Stat3 activation in STAT3-dependent human cancer cell lines. In addition, other analogs have been designed, synthesized, tested, and shown to be effective inhibitors of Stat3 dimerization.
Application
S3I-M2001 is a potential therapeutic intervention for malignant human cancer. S3I-M2001, an inhibitor of Stat3 activation, can be used to develop drugs capable of targeting cells with constitutively active Stat3, leading to tumor regression.
Advantages
• STAT3 inhibitors can be used to sensitize human cancers with constitutively active STAT3 to existing chemotherapeutic agents, potentially reducing the side effects associated with conventional, aggressive chemotherapy.
• S3I-M2001 could be made into a pharmaceutically acceptable composition and be administered to patients.
Lead Inventor
James Turkson, Ph.D.
Selected References
Fletcher S, Turkson J, Gunning PT. Molecular approaches towards the inhibition of the signal transducer and activator of transcription 3 (Stat3) protein. ChemMedChem. 2008; 3(8): 1159-68.
Siddiquee KA, Gunning PT, et al. An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects. ACS Chem Biol. 2007; 2(12): 787-98.
Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors.Cell Res. 2008; 18(2): 254-67. Review.
Contact
Attn: Svetlana Shtrom, Ph.D., MBA
University of Central Florida
Office of Research and Commercialization
12201 Research Parkway, Suite 501
Orlando, Fl 32826-3246
Phone: 407.823.5150
Fax: 407.823.3299
sshtrom@mail.ucf.edu
UCF ID # 7577/7313, 7610, 7656
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