Evidence map›Paper›PMID 30380865›Full record

ArticleJournal of medicinal chemistry2018

Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.

Gabriel Castro-Falcón, Grant S Seiler, Özlem Demir, Manoj K Rathinaswamy, David Hamelin, Reece M Hoffmann, Stefanie L Makowski, Anne-Catrin Letzel, Seth J Field, John E Burke and 2 more

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

Article in Journal of medicinal chemistry, 2018. 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
1.1field-weighted citation impact, top 22% 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, 31 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Review
  5. Dynamic structural biology at the protein membrane interface.The Journal of biological chemistry · 2019
    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 2 countries.

Gabriel Castro-FalcónCenter for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.
Grant S SeilerCenter for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.
Özlem DemirDepartment of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.ORCID 0000-0002-3317-4731
Manoj K RathinaswamyDepartment of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.
David HamelinDepartment of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.
Reece M HoffmannDepartment of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.
Stefanie L MakowskiSchool of Medicine , University of California, San Diego , La Jolla , California , 92093 , United States.
Anne-Catrin LetzelCenter for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.
Seth J FieldSchool of Medicine , University of California, San Diego , La Jolla , California , 92093 , United States.
John E BurkeDepartment of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.
Rommie E AmaroDepartment of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.ORCID 0000-0002-9275-9553
Chambers C HughesCenter for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.ORCID 0000-0002-7000-6438
Scripps Institution of Oceanography · USUniversity of California San Diego · USUniversity of Victoria · CA

Funding

National Biomedical Computation Resource - Competitive Revision SupplementP41GM103426 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI AMARO, ROMMIE E · 2012 to 2019
$14.0M
EXPERIMENTAL ENDOCRINOLOGY AND METABOLISMT32DK007044 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Amit Majithia · 1986 to 2026
$4.6M
A Structural Systems Biology Approach to Drug DiscoveryDP2OD007237 · OD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI AMARO, ROMMIE E · 2010 to 2015
$2.9M
GOLPH3 Pathway Regulation of Golgi Structure and FunctionR01GM120055 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIELD, SETH J · 2016 to 2019
$1.3M
High Throughput Screen to Identify Inhibitors of the Golgi GOLPH3 PathwayR01CA201303 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIELD, SETH J · 2016 to 2018
$1.2M
NCI NIH HHS R01 CA201303NIDDK NIH HHS T32 DK007044NIGMS NIH HHS P41 GM103426NIGMS NIH HHS R01 GM120055NIH HHS DP2 OD007237
6 · The paper itself

Abstract

Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3Kα treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu, corresponding to addition of the inhibitor and elimination of methanol. The binding pose of the inhibitor bound to PI3Kα was modeled, and hydrogen-deuterium exchange mass spectrometry experiments supported this model. Against a panel of kinases, neolymphostin showed good selectivity for PI3-kinase and mTOR. In addition, the natural product blocked AKT phosphorylation in live cells with an IC

Indexed as

Phosphoinositide-3 Kinase InhibitorsEnzyme InhibitorsEstersMolecular Docking SimulationPhosphatidylinositol 3-KinasesProtein ConformationQuinolinesTOR Serine-Threonine KinasesEnzyme InhibitorsEstersPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsQuinolinesTOR Serine-Threonine Kinases

Identifiers

PMID30380865
PMCPMC6688905
OpenAlexW2898807798

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.