Evidence map›Paper›PMID 37559436›Full record

ArticleThe Prostate2023

Third generation quinoline-3-carboxamide transcriptional disrupter of HDAC4, HIF-1α, and MEF-2 signaling for metastatic castration-resistant prostate cancer.

John T Isaacs, Susan L Dalrymple, Lizamma Antony, David Marc Rosen, Ilsa M Coleman, Peter S Nelson, Maya Kostova, Iain A Murray, Gary H Perdew, Samuel R Denmeade and 2 more

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

Article in The Prostate, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.6field-weighted citation impact, top 30% 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

5 citing papers in PubMed, 4 citations in OpenAlex.

  1. Proteogenomic Analysis of HDAC4 and HDAC5 in Uveal Melanoma.Molecular medicine (Cambridge, Mass.) · 2026
    Article
  2. Article
  3. Review
  4. Review
  5. HDAC-driven mechanisms in anticancer resistance: epigenetics and beyond.Cancer drug resistance (Alhambra, Calif.) · 2024
    Review
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

12 authors at 3 institutions in 1 country.

John T IsaacsDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University, Baltimore, Maryland, USA.ORCID 0000-0002-3854-4658
Susan L DalrympleDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University, Baltimore, Maryland, USA.
Lizamma AntonyDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University, Baltimore, Maryland, USA.
David Marc RosenDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University, Baltimore, Maryland, USA.
Ilsa M ColemanDivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Peter S NelsonDivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Maya KostovaDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University, Baltimore, Maryland, USA.
Iain A MurrayDepartment of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
Gary H PerdewDepartment of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
Samuel R DenmeadeDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University, Baltimore, Maryland, USA.ORCID 0000-0001-5442-515X
Emmanuel S AkinboyeDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University, Baltimore, Maryland, USA.
W Nathaniel BrennenDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University, Baltimore, Maryland, USA.ORCID 0000-0001-9807-7433
Johns Hopkins University · USFred Hutch Cancer Center · USPennsylvania State University · US

Funding

Translational Research Central ServicesP30CA006973 · NCI · JOHNS HOPKINS UNIVERSITY · PI WILLIAM George NELSON · 1985 to 2026
$208.6M
TRANSGENIC MODELS FOR PROSTATE CANCER AND AUTOIMMUNITYP50CA058236 · NCI · JOHNS HOPKINS UNIVERSITY · PI DENMEADE, SAMUEL R · 1992 to 2020
$43.9M
Activation of the Ah receptor and epithelial integrityR35ES028244 · NIEHS · PENNSYLVANIA STATE UNIVERSITY, THE · PI PERDEW, GARY H. · 2017 to 2024
$6.2M
A First-in-Class FAP-activated Protoxin to disrupt the Tumor-Stroma Parasitic Cycle fueling lethal Prostate Cancer ProgressionR01CA255259 · NCI · JOHNS HOPKINS UNIVERSITY · PI BRENNEN, WILLIAM NATHANIEL · 2021 to 2025
$2.1M
NCI NIH HHS P30 CA006973NCI NIH HHS P50 CA058236NCI NIH HHS R01 CA255259NIEHS NIH HHS R35 ES028244
6 · The paper itself

Abstract

backgroundThe quinoline-3-carboxamide, Tasquinimod (TasQ), is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor micro environment. In phase 3 clinical testing against metastatic castration-resistant prostate cancer(mCRPC), TasQ (1 mg/day) increased time-to-progression, but not overall survival.

methodsTasQ analogs were chemically synthesized and tested for activity compared to the parental compound. These included HDAC4 enzymatic assays, qRT-PCR and western blot analyses of gene and protein expression following treatment, in vitro and in vivo efficacy against multiple prostate cancer models including PDXs, pharmacokinetic analyses,AHR binding and agonist assays, SPR analyses of binding to HDAC4 and NCoR1, RNAseq analysis of in vivo tumors, 3D endothelial sprouting assays, and a targeted kinase screen. Genetic knockout or knockdown controls were used when appropriate.

resultsHere, we document that, on this regimen (1 mg/day), TasQ blood levels are 10-fold lower than the optimal concentration (≥2 μM) needed for anticancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that TasQ is an arylhydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1 μM to produce unwanted off-target side effects. Therefore, we screened a library of TasQ analogsto maximize on-target versus off-target activity. Using this approach, we identified ESATA-20, which has ~10-fold lower AHR agonism and 5-fold greater potency against prostate cancer patient-derived xenografts.

conclusionThis increased therapeuticindex nominates ESATA-20 as a lead candidate forclinical development as an orally active third generation quinoline-3-carboxamide analog thatretains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromisedtumor microenvironment found in mCRPC.

Indexed as

Prostatic Neoplasms, Castration-ResistantBlotting, WesternCell Line, TumorHistone DeacetylasesHumansMaleQuinolinesRepressor ProteinsTumor MicroenvironmentHDAC4 protein, humanHistone Deacetylasesquinoline-3-carboxamideQuinolinesRepressor Proteinsaryl hydrocarbon receptordrug developmentHDAC4prostate cancertasquinimod

Identifiers

PMID37559436
PMCPMC10559933
OpenAlexW4385715336

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.