Evidence map›Paper›PMID 28236510›Full record

ArticleBioorganic & medicinal chemistry2017

A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids.

Mingzhao Zhu, Wayne D Harshbarger, Omar Robles, Joanna Krysiak, Kenneth G Hull, Sung Wook Cho, Robyn D Richardson, Yanyan Yang, Andres Garcia, Lindsey Spiegelman and 10 more

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

Article in Bioorganic & medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
0.7field-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

6 citing papers in PubMed, 14 citations in OpenAlex.

  1. Covalent Inhibition of thePharmaceuticals (Basel, Switzerland) · 2022
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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

20 authors at 4 institutions in 2 countries.

Mingzhao ZhuDepartment of Chemistry & Biochemistry and CPRIT Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX 76706, USA.
Wayne D HarshbargerDepartment of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA.
Omar RoblesDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Joanna KrysiakDepartment of Chemistry, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
Kenneth G HullDepartment of Chemistry & Biochemistry and CPRIT Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX 76706, USA.
Sung Wook ChoDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Robyn D RichardsonSanford Burnham Medical Research Institute, La Jolla, CA, USA.
Yanyan YangDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Andres GarciaDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Lindsey SpiegelmanDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Bianca RamirezDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Christopher T WilsonDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Ju Anne YauDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
James T MooreDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Caitlen B WalkerDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
James C SacchettiniDepartment of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA.
Wenshe R LiuDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Stephan A SieberDepartment of Chemistry, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
Jeffrey W SmithSanford Burnham Medical Research Institute, La Jolla, CA, USA.
Daniel RomoDepartment of Chemistry & Biochemistry and CPRIT Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX 76706, USA. Electronic address: Daniel_Romo@baylor.edu.
Texas A&M University · USBaylor University · USSanford Burnham Prebys Medical Discovery Institute · USTechnical University of Munich · DE

Funding

Synthetic/Mechanistic Studies of Bioactive Marine AgentsR37GM052964 · NIGMS · TEXAS A&M UNIVERSITY · PI ROMO, DANIEL · 2009 to 2019
$3.6M
Lead Optimization of Novel Inhibitors of the Thioesterase Domain of FASNR01CA188694 · NCI · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI COSFORD, NICHOLAS DAVID, SMITH, JEFFREY W · 2014 to 2016
$2.3M
Phage Display with Two Genetically Incorporated Noncanonical Amino AcidsR01CA161158 · NCI · TEXAS A&M UNIVERSITY · PI LIU, WENSHE RAY · 2011 to 2015
$1.6M
NOVEL ANTICANCER FATTY ACID SYNTHASE INHIBITORSR01CA106582 · NCI · TEXAS A&M UNIVERSITY SYSTEM · PI ROMO, DANIEL · 2004 to 2007
$909k
NCI NIH HHS R01 CA106582NCI NIH HHS R01 CA161158NCI NIH HHS R01 CA188694NIGMS NIH HHS R37 GM052964
6 · The paper itself

Abstract

The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, β-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and fatty acid synthase-thioesterase (FAS-TE) enabling a new approach for the development of drug-candidates with potential to overcome resistance.

Indexed as

Cell ProliferationCell SurvivalDose-Response Relationship, DrugFatty Acid SynthasesHeLa CellsHumansLactonesMCF-7 CellsMolecular StructureOrlistatPeptidesProteasome Endopeptidase ComplexStructure-Activity Relationshipbelactosin CFatty Acid SynthasesLactonesOrlistatPeptidesProteasome Endopeptidase ComplexActivity-based protein profilingBeta-lactonesInhibitorSerum stabilityStructure-activity relationship studies

Identifiers

PMID28236510
PMCPMC5522751
OpenAlexW2576871292

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.