Evidence map›Paper›PMID 40033556›Full record

ArticleJournal of medicinal chemistry2025

Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia.

Purav P Vagadia, Javier Izquierdo-Ferrer, Candice Mazewski, Gavin Blyth, Elspeth M Beauchamp, Matthew R Clutter, Charlotte L Stern, Rama K Mishra, Dominik Nahotko, Sara Small and 3 more

Abstract read
In one paragraph

Article in Journal of medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
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

3 citing papers in PubMed.

  1. Article
  2. Article
  3. 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

13 authors.

Purav P VagadiaDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
Javier Izquierdo-FerrerDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.ORCID 0000-0002-1086-1096
Candice MazewskiRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.
Gavin BlythRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.
Elspeth M BeauchampRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.ORCID 0009-0007-3180-2742
Matthew R ClutterRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.
Charlotte L SternDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.ORCID 0000-0002-9491-289X
Rama K MishraDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.ORCID 0000-0003-3608-2602
Dominik NahotkoRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.
Sara SmallRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.
Frank EckerdtRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.
Leonidas C PlataniasRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.
Gary E SchiltzDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.ORCID 0000-0003-4180-5051

Funding

Tumor Environment and Metastasis (TEAM) Research ProgramP30CA060553 · NCI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Devalingam Mahalingam · 1993 to 2026
$153.9M
Targeting Novel Protein Complexes for the Treatment of Acute Myeloid LeukemiaR01CA121192 · NCI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI PLATANIAS, LEONIDAS C. · 2006 to 2023
$4.1M
Development of Novel MNK Inhibitors for Treating GlioblastomaR01NS113425 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI PLATANIAS, LEONIDAS C., SCHILTZ, GARY E · 2019 to 2023
$2.5M
Echo Acoustic Liquid Handler for High Throughput Analysis LabS10OD023681 · OD · NORTHWESTERN UNIVERSITY · PI WEISS, ERIC LYLE · 2018 to 2018
$550k
Sciex 6500+ QTrap Mass SpectrometerS10OD030332 · OD · SCRIPPS FLORIDA · PI CAMERON, MICHAEL DARIN · 2021 to 2021
$486k
NCI NIH HHS P30 CA060553NCI NIH HHS R01 CA121192NIH HHS S10 OD023681NIH HHS S10 OD030332NINDS NIH HHS R01 NS113425
6 · The paper itself

Abstract

MNK activity is regulated by the p38 and Erk MAPK pathways. Phosphorylation of MNK leads to its activation and binding to the eIF4G/eIF4E complex. MNK then phosphorylates eIF4E at Ser209, whose activation is associated with oncogene translation, leading to tumorigenesis. Given this important role for eIF4E in tumorigenesis, MNK inhibition with novel small molecule inhibitors could be a promising strategy to combat AML, which continues to be an area of unmet medical need. Here, we report the medicinal optimization of a series of novel inhibitors and their evaluation of their effects on eIF4E and leukemia cell viability. We discovered a class of ether-containing compounds with a high MNK1/2 selectivity. These MNK inhibitors show good potency in reducing cell viability and colony formation and have desirable pharmacokinetic properties. X-ray cocrystallization was accomplished to confirm the binding mode of our inhibitors and aid in future optimization.

Indexed as

Protein Kinase InhibitorsProtein Serine-Threonine KinasesAnimalsAntineoplastic AgentsCell Line, TumorCell SurvivalCrystallography, X-RayDrug DiscoveryEukaryotic Initiation Factor-4EHumansIntracellular Signaling Peptides and ProteinsLeukemiaModels, MolecularStructure-Activity RelationshipAntineoplastic AgentsEukaryotic Initiation Factor-4EIntracellular Signaling Peptides and ProteinsMKNK1 protein, humanMKNK2 protein, humanProtein Kinase InhibitorsProtein Serine-Threonine Kinases

Identifiers

PMID40033556
PMCPMC12746474

What OpenQuestion holds

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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.