Carboxyl-terminal binding protein (CtBP) is a co-repressor for many transcription factors and was initially recognized as an adenoviral E1A-binding protein. CtBP expression is low or undetectable in most adult tissues. We found that CtBP is abnormally over expressed in multiple human cancers. For example, it is over- expressed in over 50% of primary lung cancer and 90% of metastatic lesions. We also observed frequent CtBP over-expression in breast tumor, head and neck cancer, renal carcinoma, and melanoma. We have found that CtBP over expression suppresses the expression of genes critical for cell death, leading to cancer development. Moreover, we found that reducing CtBP in lung cancer cells induced cancer cell death, and suppressed human tumor growth in a mouse model. Based on these data, we hypothesize that decreasing CtBP's function represents an attractive therapy for multiple cancer types with limited side effects. CtBP interacts with E1A and other transcription factors through a conserved peptide motif. Detailed biochemical/structural studies reveal that it is feasible to use small molecule compounds to inhibit the interaction between CtBP and the transcription factors it binds. We have developed an Alpha Screen based HTS assay targeting the CtBP/E1A interaction. We propose to perform a large scale high throughput screening using the NIH MLPCN compounds to identify inhibitors of the interaction between CtBP and the transcription factors it binds. We plan to test these inhibitors for their potential as therapeutic tools to inhibit CtBP-mediated tumor genesis and metastasis. These inhibitors can also be used as valuable chemical probes for functional studies of CtBP.
Carboxyl-terminal binding protein (CtBP) is a co-repressor and a foe of multiple tumor suppressors. In most adult tissues, CtBP expression is low. Recently, we found CtBP is over-expressed in over 50% of primary lung cancer and 90% of metastatic lesions. We also observed frequent CtBP over-expression in breast tumor, head and neck cancer, and melanoma, suppressing the transcription of well known tumor suppressors and potentially contributing to the tumorigenesis of multiple solid cancers. Moreover, we have shown that CtBP knockdown triggers apoptosis of tumor cells independent of tumor suppressors, thus providing an ideal pharmacological target. In this application, we aim to identify the effective blockers for CtBP function both in vitro and in vivo. We believe this approach be effective and less harmful to normal tissue due to the tumor- specific activity of CtBP.
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