Evidence map›Paper›PMID 34802837›Full record

ArticleEuropean journal of medicinal chemistry2022

Structural effects of morpholine replacement in ZSTK474 on Class I PI3K isoform inhibition: Development of novel MEK/PI3K bifunctional inhibitors.

Marcian E Van Dort, Youngsoon Jang, Christopher A Bonham, Kevin Heist, Dilrukshika S W Palagama, Lucas McDonald, Edward Z Zhang, Thomas L Chenevert, Gary D Luker, Brian D Ross

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

Article in European journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed, 1 pooled it
0.6field-weighted citation impact, top 35% 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

3 citing papers in PubMed, 1 synthesis or guideline pooled it, 10 citations in OpenAlex.

  1. Pooled it
  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

10 authors at 1 institution in 1 country.

Marcian E Van DortCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: mvandort@umich.edu.
Youngsoon JangCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: jyoungso@umich.edu.
Christopher A BonhamCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: bonhachr@umich.edu.
Kevin HeistCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: heistka@umich.edu.
Dilrukshika S W PalagamaCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: dilruksp@umich.edu.
Lucas McDonaldCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: mcdonalu@umich.edu.
Edward Z ZhangCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: edzhang@umich.edu.
Thomas L ChenevertCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: tlchenev@umich.edu.
Gary D LukerCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: gluker@umich.edu.
Brian D RossCenter for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA; Department of Biological Chemistry, The University of Michigan Medical School, MI, 48109, USA. Electronic address: bdross@umich.edu.
University of Michigan · US

Funding

XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Alexey I Nesvizhskii · 1988 to 2026
$178.2M
Imaging of Hematologic and Oncologic DisordersR35CA197701 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ROSS, BRIAN D. · 2016 to 2022
$5.9M
University of Michigan Quantitative Co-Clinical Imaging Research ResourceU24CA237683 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHENEVERT, THOMAS L, LUKER, GARY D · 2019 to 2023
$3.1M
Imaging Disease Heterogeneity and Response to Therapy in MyelofibrosisR01CA238023 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LUKER, GARY D, ROSS, BRIAN D. · 2019 to 2023
$3.1M
NCI NIH HHS P30 CA046592NCI NIH HHS R01 CA238023NCI NIH HHS R35 CA197701NCI NIH HHS U24 CA237683
6 · The paper itself

Abstract

Established roles for PI3K and MAPK signaling pathways in tumorigenesis has prompted extensive research towards the discovery of small-molecule inhibitors as cancer therapeutics. However, significant compensatory regulation exists between these two signaling cascades, leading to redundancy among survival pathways. Consequently, initial clinical trials aimed at either PI3K or MEK inhibition alone have proven ineffective and highlight the need for development of targeted and innovative therapeutic combination strategies. We designed a series of PI3K inhibitor derivatives wherein a single morpholine group of the PI3K inhibitor ZSTK474 was substituted with a variety of 2-aminoethyl functional groups. Analogs with pendant hydroxyl or methoxy groups maintained low nanomolar inhibition towards PI3Kα, PI3Kγ, and PI3Kδ isoforms in contrast to those with pendant amino groups which were significantly less inhibitory. Synthesis of prototype PI3K/MEK bifunctional inhibitors (6r, 6s) was guided by the structure-activity data, where a MEK-targeting inhibitor was tethered directly via a short PEG linker to the triazine core of the PI3K inhibitor analogs. These compounds (6r, 6s) displayed nanomolar inhibition towards PI3Kα, δ, and MEK (IC

Indexed as

AnimalsBinding SitesCell Line, TumorCell ProliferationDisease Models, AnimalHumansMiceMice, TransgenicMitogen-Activated Protein Kinase KinasesMolecular Docking SimulationMorpholinesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPrimary MyelofibrosisProtein IsoformsStructure-Activity RelationshipMitogen-Activated Protein Kinase KinasesmorpholineMorpholinesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein IsoformsTriazinesZSTK474Bifunctional MEK/PI3K inhibitorPI3K isoform inhibitionZSTK474

Identifiers

PMID34802837
PMCPMC8792322
OpenAlexW3213493688

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.