Design, synthesis, and biological evaluation of substrate-competitive inhibitors of C-terminal Binding Protein (CtBP)

Bioorg Med Chem. 2016 Jun 15;24(12):2707-15. doi: 10.1016/j.bmc.2016.04.037.

Sudha Korwar ¹, Benjamin L Morris ², Hardik I Parikh ¹, Robert A Coover ¹, Tyler W Doughty ³, Ian M Love ², Brendan J Hilbert ⁴, William E Royer Jr ⁴, Glen E Kellogg ¹, Steven R Grossman ⁵, Keith C Ellis ⁶

Affiliations

1 Department of Medicinal Chemistry, School of Pharmacy, The Institute for Structural Biology, Drug Discovery, and Development, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States.
2 Division of Hematology, Oncology, & Palliative Care, Department of Human and Molecular Genetics, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States.
3 Department of Molecular, Cell, & Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, United States.
4 Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, United States.
5 Division of Hematology, Oncology, & Palliative Care, Department of Human and Molecular Genetics, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: steven.grossman@vcuhealth.org.
6 Department of Medicinal Chemistry, School of Pharmacy, The Institute for Structural Biology, Drug Discovery, and Development, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: kcellis@vcu.edu.

PMID: 27156192 DOI: 10.1016/j.bmc.2016.04.037

Abstract

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=0.24μM). A structure-activity relationship study of this compound further identified the 4-chloro- (IC50=0.18μM) and 3-chloro- (IC50=0.17μM) 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.

Keywords

C-terminal Binding Protein; CtBP; Dehydrogenase; Hydroxyimine; MTOB; Oxime; Transcriptional co-repressor; Tumor suppressor gene.

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