Evidence map›Paper›PMID 31036695›Full record

ArticleMolecular pharmacology2019

Active-Site Tryptophan, the Target of Antineoplastic C-Terminal Binding Protein Inhibitors, Mediates Inhibitor Disruption of CtBP Oligomerization and Transcription Coregulatory Activities.

M Michael Dcona, Priyadarshan K Damle, Francisco Zarate-Perez, Benjamin L Morris, Zaid Nawaz, Michael J Dennis, Xiaoyan Deng, Sudha Korwar, Sahib J Singh, Keith C Ellis and 4 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
0.5field-weighted citation impact, top 36% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 56 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Review
  6. Article
  7. Review
  8. Cryo-EM structure of CtBP2 confirms tetrameric architecture.Structure (London, England : 1993) · 2021
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 1 institution in 2 countries.

M Michael DconaDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).ORCID 0000-0001-9418-0775
Priyadarshan K DamleDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Francisco Zarate-PerezDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Benjamin L MorrisDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Zaid NawazDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Michael J DennisDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Xiaoyan DengDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Sudha KorwarDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Sahib J SinghDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Keith C EllisDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
William E RoyerDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Dipankar BandyopadhyayDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Carlos EscalanteDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.).
Steven R GrossmanDepartments of Internal Medicine (M.M.D., P.K.D., Z.N., M.J.D., S.J.S., S.R.G.), Human and Molecular Genetics (B.L.M., S.R.G.), Physiology and Biophysics (F.Z.-P., C.E.), Medicinal Chemistry (S.K., K.C.E.), and Biostatistics (X.D., D.B.) and Massey Cancer Center (K.C.E., D.B., C.E., S.R.G.), Virginia Commonwealth University, Richmond, Virginia; and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (W.E.R.) steven.grossman@vcuhealth.org.
University of Massachusetts Chan Medical School · US

Funding

Virus Vector Shared ResourceP30CA016059 · NCI · VIRGINIA COMMONWEALTH UNIVERSITY · PI Kim Felder Rhoads · 1985 to 2026
$51.0M
Structure-based characterization of CtBP as a therapeutic target in cancerR01GM119014 · NIGMS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ROYER, WILLIAM E · 2017 to 2020
$1.3M
NCI NIH HHS P30 CA016059NIGMS NIH HHS R01 GM119014
6 · The paper itself

Abstract

C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenases often overexpressed in multiple solid tumors, including breast, colon, and ovarian cancer, and associated with poor survival. CtBPs act by repressing expression of genes responsible for apoptosis (e.g., PUMA, BIK) and metastasis-associated epithelial-mesenchymal transition (e.g., CDH1), and by activating expression of genes that promote migratory and invasive properties of cancer cells (e.g., TIAM1) and genes responsible for enhanced drug resistance (e.g., MDR1). CtBP's transcriptional functions are also critically dependent on oligomerization and nucleation of transcriptional complexes. Recently, we have developed a family of CtBP dehydrogenase inhibitors, based on the parent 2-hydroxyimino-3-phenylpropanoic acid (HIPP), that specifically disrupt cancer cell viability, abrogate CtBP's transcriptional function, and block polyp formation in a mouse model of intestinal polyposis that depends on CtBP's oncogenic functions. Crystallographic analysis revealed that HIPP interacts with CtBP1/2 at a conserved active site tryptophan (W318/324; CtBP1/2) that is unique among eukaryotic D2-dehydrogenases. To better understand the mechanism of action of HIPP-class inhibitors, we investigated the contribution of W324 to CtBP2's biochemical and physiologic activities utilizing mutational analysis. Indeed, W324 was necessary for CtBP2 self-association, as shown by analytical ultracentrifugation and in vivo cross-linking. Additionally, W324 supported CtBP's association with the transcriptional corepressor CoREST, and was critical for CtBP2 induction of cell motility. Notably, the HIPP derivative 4-chloro-HIPP biochemically and biologically phenocopied mutational inactivation of CtBP2 W324. Our data support further optimization of W318/W324-interacting CtBP dehydrogenase inhibitors that are emerging as a novel class of cancer cell-specific therapeutic.

Indexed as

Alcohol OxidoreductasesAnimalsAntineoplastic AgentsCatalytic DomainCell Line, TumorCell MovementCell SurvivalDNA-Binding ProteinsEnzyme InhibitorsEpithelial-Mesenchymal TransitionGene Expression Regulation, NeoplasticHCT116 CellsHumansHydroxylaminesIntestinal PolyposisMiceAlcohol OxidoreductasesAntineoplastic AgentsC-terminal binding proteinDNA-Binding ProteinsEnzyme InhibitorsHydroxylaminesPhenylpropionatesTryptophan

Identifiers

PMID31036695
PMCPMC6560337
OpenAlexW2943805842

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.