Signal transducer and activators of transcription 3 (Stat3) is a member of the STAT family of transcription factors that relate signals from extracellular signaling protein receptors on the plasma membrane directly to the nucleus. Stat3 relates signals from IL-6 family members and growth factors such as EGF and PDGF. Stat3 is constitutively activated in several cancer types, such as breast, prostate, ovarian, leukemia, multiple myeloma, etc. Introduction of antisense and dominant negative gene constructs into tumor cells lines results in growth arrest and apoptosis. Thus Stat3 is a target for anticancer drug design. Our overall hypothesis is that small molecule Stat3 inhibitors targeted to the SH2 domain will be effective chemotherapeutic agents for the treatment of cancer. In the first submission of this grant we found a high affinity phospho-peptide template, Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH2, and from this developed a peptidomimetic inhibitor. We showed that stabilized phosphopeptide sequences and peptidomimetic prod rugs were able to inhibit Stat3 activity in cellular assays and we demonstrated growth arrest of breast tumor and multiple myeloma cells in culture, although at high concentrations (10-25 microM). In this proposal we aim to increase the affinity of our inhibitors for Stat3 to make them more potent chemotherapeutic agents.
Our specific aims are (1) Synthesize targeted libraries of our inhibitor incorporating conformationally constrained building blocks to gain information on the conformation of our compounds bound to Stat3 and to increase affinity, (2) Determine the structure of our inhibitors bound to Stat3 using X-ray crystallography for use in structure- guided inhibitor design (3) Assay our compounds as inhibitors of Stat3 activity and tumor cell growth in culture (4) Test our compounds as anti-cancer agents in tumor models in mice. ? ? ? ?
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