Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 24, Issue 12, Pages 2707-2715Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.04.037
Keywords
C-terminal Binding Protein; CtBP; MTOB; Hydroxyimine; Oxime; Transcriptional co-repressor; Dehydrogenase; Tumor suppressor gene
Funding
- VCU Massey Cancer Center
- NIH-NCI Cancer Center [P30 CA016059]
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C-terminal Binding Protein (CtBP) is a transcriptional co-regulator that downregulates the expression of many tumor-suppressor genes. Utilizing a crystal structure of CtBP with its substrate 4-methylthio-2-oxobutyric acid (MTOB) and NAD(+) as a guide, we have designed, synthesized, and tested a series of small molecule inhibitors of CtBP. From our first round of compounds, we identified 2-(hydroxyimino)-3-phenylpropanoic acid as a potent CtBP inhibitor (IC50 = 0.24 mu M). A structure-activity relationship study of this compound further identified the 4-chloro- (IC50 = 0.18 mu M) and 3-chloro- (IC50 = 0.17 mu M) analogues as additional potent CtBP inhibitors. Evaluation of the hydroxyimine analogues in a short-term cell growth/viability assay showed that the 4-chloro- and 3-chloro-analogues are 2-fold and 4-fold more potent, respectively, than the MTOB control. A functional cellular assay using a CtBP-specific transcriptional readout revealed that the 4-chloro- and 3-chloro-hydroxyimine analogues were able to block CtBP transcriptional repression activity. This data suggests that substrate-competitive inhibition of CtBP dehydrogenase activity is a potential mechanism to reactivate tumor-suppressor gene expression as a therapeutic strategy for cancer. (C) 2016 Elsevier Ltd. All rights reserved.
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