biostudies-literatureKorwar SNCI NIH HHS2707-15https://www.ebi.ac.uk/biostudies/studies/S-EPMC4993153biostudies-literatureUnknown24(12)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?M). A structure-activity relationship study of this compound further identified the 4-chloro- (IC50=0.18?M) and 3-chloro- (IC50=0.17?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.Bioorganic & medicinal chemistryDesign, synthesis, and biological evaluation of substrate-competitive inhibitors of C-terminal Binding Protein (CtBP).PMC4993153P30 CA016059Ellis KCCoover RAKellogg GEKorwar SLove IMGrossman SRParikh HIRoyer WEDoughty TWHilbert BJMorris BLfalseDesign, synthesis, and biological evaluation of substrate-competitive inhibitors of C-terminal Binding Protein (CtBP).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?M). A structure-activity relationship study of this compound further identified the 4-chloro- (IC50=0.18?M) and 3-chloro- (IC50=0.17?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.2016-01-01T00:00:00Z2016 Jun2021-02-19T21:55:23Z2019-03-27T02:21:11ZS-EPMC49931532715619210.1016/j.bmc.2016.04.037