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BioAssay: AID 651737

qHTS Assay for Inhibitors of the CtBP/E1A Interaction

Carboxyl-terminal binding protein (CtBP) is a co-repressor for many transcription factors. CtBP was initially recognized as an adenoviral E1A-binding protein and its over-activation, in combination with mutated Ras, leads to tumorigenesis and metastasis, suggesting CtBP plays a critical role in oncogenesis. Our studies have shown that CtBP is overexpressed in multiple human cancers, including more ..
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AID: 651737
Data Source: NCGC (CTBP000)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2012-10-31
Target
Depositor Specified Assays
AIDNameTypeComment
651724qHTS Assay for Inhibitors of the CtBP/E1A Interactionscreening
Description:
Carboxyl-terminal binding protein (CtBP) is a co-repressor for many transcription factors. CtBP was initially recognized as an adenoviral E1A-binding protein and its over-activation, in combination with mutated Ras, leads to tumorigenesis and metastasis, suggesting CtBP plays a critical role in oncogenesis. Our studies have shown that CtBP is overexpressed in multiple human cancers, including lung, breast, and head and neck cancers. In particular, it is over-expressed in 50% of primary lung cancer and 90% of metastatic lesions. CtBP suppresses epithelial-specific genes as well as genes critical for apoptosis, providing the underlying molecular mechanism for its role in tumorigenesis. Moreover, we found that CtBP-knockdown in lung cancer cells induced p53-independent apoptosis, and suppressed human tumor growth in mouse model. Based on the above data, we hypothesize that 1) CtBP suppresses the pro-apoptotic and epithelial genes, therefore overexpressed CtBP in human cancer cells increases EMT and cancer survival; 2) decreasing CtBP's function represents a targeted therapy for lung cancer and potentially multiple cancer types. As a co-repressor, CtBP binds to E1A and other transcription factors through a conserved peptide motif to carry out its action. Inhibiting this interaction using small molecules can potentially serve as effective cancer therapeutics.

To this end, we have developed a homogenous AlphaScreen assay targeting the CtBP/E1A interaction. We performed a large scale HTS of the Molecular Libraries Small Molecule Repository (MLSMR) to identify inhibitors of the CtBP/E1A interaction as potential anti-cancer therapeutics. Compounds identified can also be used as chemical probes to better understand the biological functions of CtBP.

NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Centers Network [MLPCN]

MLPCN Grant: DA033982
Assay Submitter (PI): Rui Zhao, University of Colorado Denver
Protocol
Please see linked AIDs for detailed protocols.
Comment
This project is on-going and will be updated at a later point.
Additional Information
Grant Number: DA033982

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