Summary of Study ST003436

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001941. The data can be accessed directly via it's Project DOI: 10.21228/M8TM76 This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST003436
Study TitlePharmacokinetics of Fasnall in NSG mice
Study SummaryFasnall concentrations in plasma, heart, liver, and brain of NSG mice were monitored after 10 mg/kg intraperitoneal bolus.
Institute
Wistar Institute
DepartmentMolecular and Cellular Oncogenesis Program, Ellen and Ronald Caplan Cancer Center
LaboratorySchug's Lab
Last NameMukha
First NameDzmitry
Address3601 Spruce St, Philadelphia, PA 19104, USA
Emaildmukha@wistar.org
Phone+12154956903
Submit Date2024-08-21
Num Groups27
Total Subjects82
PublicationsSubmission Pending
Raw Data AvailableYes
Raw Data File Type(s)mzML, wiff
Analysis Type DetailLC-MS
Release Date2024-09-12
Release Version1
Dzmitry Mukha Dzmitry Mukha
https://dx.doi.org/10.21228/M8TM76
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001941
Project DOI:doi: 10.21228/M8TM76
Project Title:The shutdown of NADH oxidation via Respiratory Complex I mimics fatty acid biosynthesis inhibition
Project Type:LC-MS Quantitative Analysis
Project Summary:Proliferating cancer cells actively utilize anabolic processes for biomass production, including de novo biosynthesis of amino acids, nucleotides, and fatty acids. The key enzyme of the fatty acid biosynthesis pathway, fatty acid synthase (FASN), is widely recognized as a promising therapeutic target in cancer and other health conditions. Here, we establish a metabolic signature of FASN inhibition using a panel of pharmacological inhibitors (GSK2194069, TVB-2640, TVB-3166, C75, cerulenin, and Fasnall). We find that the activity of some commonly used FASN inhibitors is inconsistent with the metabolic signature of FASN inhibition (accumulation of malonate, succinate, malonyl coenzyme A, succinyl coenzyme A, and other metabolic perturbations). Moreover, we show that one of these putative FASN inhibitors, Fasnall, is a respiratory Complex I inhibitor that mimics FASN inhibition through NADH accumulation and consequent depletion of the tricarboxylic acid cycle metabolites. We demonstrate that Fasnall impairs tumor growth in several oxidative phosphorylation-dependent cancer models, including combination therapy-resistant melanoma patient-derived xenografts. Fasnall administration does not reproduce neurological side effects in mice reported for other Complex I inhibitors. Our results have significant implications for understanding the FASN role in human health and disease and provide evidence of therapeutic potential for Complex I inhibitors with fast systemic clearance. Our findings also highlight the continuing need for validation of small molecule inhibitors to distinguish high-quality chemical probes and to expand the understanding of their application.
Institute:Wistar Institute
Department:Molecular and Cellular Oncogenesis Program, Ellen and Ronald Caplan Cancer Center
Laboratory:Schug's Lab
Last Name:Mukha
First Name:Dzmitry
Address:3601 Spruce St., Philadelphia, Pennsylvania 19104, USA
Email:dmukha@wistar.org
Phone:+12154956903
Funding Source:This work was supported by grants from the National Institutes of Health (NIH) National Cancer Institute (NCI) DP2 CA249950-01 (Z.T.S.), NIH NCI P01 CA114046 (Z.T.S.), Melanoma Research Foundation 717173 (Z.T.S.), and Susan G. Komen CCR19608782 (Z.T.S.).
Publications:Submission Pending
Contributors:Dzmitry Mukha, Jena Dessain, Seamus O’Connor, Katherine Pniewski, Fabrizio Bertolazzi, Jeet Patel, Mary Mullins, Zachary T. Schug

Subject:

Subject ID:SU003563
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Genotype Strain:NOD Scid Gamma (NSG)
Age Or Age Range:3 months
Weight Or Weight Range:24-33 g
Gender:Female
Animal Animal Supplier:Wistar Animal Facility
Animal Housing:Wistar Animal Facility
Animal Feed:Standard chow diet

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Sample source Sample Type Drug Treatment Time post-injection
SA37817472 F12 RedFBS-based standard FBS-based standard NA NA
SA37817560 F10 BlueFBS-based standard FBS-based standard NA NA
SA37817661 F09 BlueFBS-based standard FBS-based standard NA NA
SA37817762 F08 BlueFBS-based standard FBS-based standard NA NA
SA37817863 F07 BlueFBS-based standard FBS-based standard NA NA
SA37817964 F06 BlueFBS-based standard FBS-based standard NA NA
SA37818066 F04 BlueFBS-based standard FBS-based standard NA NA
SA37818167 F03 Blue 25 uMFBS-based standard FBS-based standard NA NA
SA37818268 F02 Blue 50 uMFBS-based standard FBS-based standard NA NA
SA37818369 F01 Blue 100 uM Fasnall in dFBSFBS-based standard FBS-based standard NA NA
SA37818473 F11 RedFBS-based standard FBS-based standard NA NA
SA37818558 F12 BlueFBS-based standard FBS-based standard NA NA
SA37818674 F10 RedFBS-based standard FBS-based standard NA NA
SA37818775 F09 RedFBS-based standard FBS-based standard NA NA
SA37818876 F08 RedFBS-based standard FBS-based standard NA NA
SA37818977 F07 RedFBS-based standard FBS-based standard NA NA
SA37819078 F06 RedFBS-based standard FBS-based standard NA NA
SA37819179 F05 RedFBS-based standard FBS-based standard NA NA
SA37819280 F04 RedFBS-based standard FBS-based standard NA NA
SA37819381 F03 Red 25 uMFBS-based standard FBS-based standard NA NA
SA37819482 F02 Red 50 uMFBS-based standard FBS-based standard NA NA
SA37819583 F01 Red 100 uM Fasnall in dFBSFBS-based standard FBS-based standard NA NA
SA37819659 F11 BlueFBS-based standard FBS-based standard NA NA
SA37819765 F05 BlueFBS-based standard FBS-based standard NA NA
SA378201126 Fasnall PK 1891 15 min BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 15 min
SA378202125 Fasnall PK 1892 15 min BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 15 min
SA378203124 Fasnall PK 1893 15 min BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 15 min
SA378198122 Fasnall PK 1895 1 hr BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 1 h
SA378199123 Fasnall PK 1894 1 hr BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 1 h
SA378200121 Fasnall PK 1896 1 hr BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 1 h
SA378204118 Fasnall PK 1899 2 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 2 h
SA378205120 Fasnall PK 1897 2 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 2 h
SA378206119 Fasnall PK 1898 2 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 2 h
SA378207115 Fasnall PK 1902 3 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 3 h
SA378208116 Fasnall PK 1901 3 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 3 h
SA378209117 Fasnall PK 1900 3 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 3 h
SA378210112 Fasnall PK 1905 4 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 4 h
SA378211113 Fasnall PK 1904 4 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 4 h
SA378212114 Fasnall PK 1903 4 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 4 h
SA378213109 Fasnall PK 1908 6 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 6 h
SA378214110 Fasnall PK 1907 6 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 6 h
SA378215111 Fasnall PK 1906 6 hrs BrainMurine brain Tissue metabolite extract 10 mg/kg Fasnall 6 h
SA378216108 Fasnall PK Control BrainMurine brain Tissue metabolite extract Control NA
SA378217107 Fasnall PK Control BrainMurine brain Tissue metabolite extract Control NA
SA378218106 Fasnall PK Control BrainMurine brain Tissue metabolite extract Control NA
SA37822257 Fasnall PK 1891 15 min HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 15 min
SA37822355 Fasnall PK 1893 15 min HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 15 min
SA37822456 Fasnall PK 1892 15 min HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 15 min
SA37821953 Fasnall PK 1895 1 hr HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 1 h
SA37822052 Fasnall PK 1896 1 hr HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 1 h
SA37822154 Fasnall PK 1894 1 hr HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 1 h
SA37822549 Fasnall PK 1899 2 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 2 h
SA37822650 Fasnall PK 1898 2 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 2 h
SA37822751 Fasnall PK 1897 2 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 2 h
SA37822847 Fasnall PK 1901 3 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 3 h
SA37822948 Fasnall PK 1900 3 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 3 h
SA37823046 Fasnall PK 1902 3 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 3 h
SA37823144 Fasnall PK 1904 4 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 4 h
SA37823243 Fasnall PK 1905 4 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 4 h
SA37823345 Fasnall PK 1903 4 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 4 h
SA37823442 Fasnall PK 1906 6 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 6 h
SA37823541 Fasnall PK 1907 6 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 6 h
SA37823640 Fasnall PK 1908 6 hrs HeartMurine heart Tissue metabolite extract 10 mg/kg Fasnall 6 h
SA37823739 Fasnall PK Control HeartMurine heart Tissue metabolite extract Control NA
SA37823838 Fasnall PK Control HeartMurine heart Tissue metabolite extract Control NA
SA37823937 Fasnall PK Control HeartMurine heart Tissue metabolite extract Control NA
SA378243104 Fasnall PK 1892 15 min LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 15 min
SA378244103 Fasnall PK 1893 15 min LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 15 min
SA378245105 Fasnall PK 1891 15 min LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 15 min
SA378240101 Fasnall PK 1895 1 hr LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 1 h
SA378241100 Fasnall PK 1896 1 hr LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 1 h
SA378242102 Fasnall PK 1894 1 hr LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 1 h
SA37824699 Fasnall PK 1899 2 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 2 h
SA37824798 Fasnall PK 1897 2 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 2 h
SA37824897 Fasnall PK 1899 2 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 2 h
SA37824995 Fasnall PK 1901 3 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 3 h
SA37825096 Fasnall PK 1900 3 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 3 h
SA37825194 Fasnall PK 1902 3 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 3 h
SA37825291 Fasnall PK 1905 4 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 4 h
SA37825393 Fasnall PK 1903 4 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 4 h
SA37825492 Fasnall PK 1904 4 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 4 h
SA37825588 Fasnall PK 1908 6 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 6 h
SA37825689 Fasnall PK 1907 6 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 6 h
SA37825790 Fasnall PK 1906 6 hrs LiverMurine liver Tissue metabolite extract 10 mg/kg Fasnall 6 h
SA37825885 Fasnall PK Control LiverMurine liver Tissue metabolite extract Control NA
SA37825986 Fasnall PK Control LiverMurine liver Tissue metabolite extract Control NA
SA37826087 Fasnall PK Control LiverMurine liver Tissue metabolite extract Control NA
SA37826116 Plasma Fasnall Std 50 ug/mlMurine plasma Plasma-based standard NA NA
SA37826215 Plasma Fasnall Std 25 ug/mlMurine plasma Plasma-based standard NA NA
SA37826314 Plasma Fasnall Std 10 ug/mlMurine plasma Plasma-based standard NA NA
SA37826403 Plasma Fasnall Std 0.2 ng/mlMurine plasma Plasma-based standard NA NA
SA37826504 Plasma Fasnall Std 1 ng/mlMurine plasma Plasma-based standard NA NA
SA37826605 Plasma Fasnall Std 2 ng/mlMurine plasma Plasma-based standard NA NA
SA37826706 Plasma Fasnall Std 10 ng/mlMurine plasma Plasma-based standard NA NA
SA37826807 Plasma Fasnall Std 20 ng/mlMurine plasma Plasma-based standard NA NA
SA37826909 Plasma Fasnall Std 250 ng/mlMurine plasma Plasma-based standard NA NA
SA37827010 Plasma Fasnall Std 500 ng/mlMurine plasma Plasma-based standard NA NA
SA37827111 Plasma Fasnall Std 1 ug/mlMurine plasma Plasma-based standard NA NA
SA37827212 Plasma Fasnall Std 2.5 ug/mlMurine plasma Plasma-based standard NA NA
SA37827313 Plasma Fasnall Std 5 ug/mlMurine plasma Plasma-based standard NA NA
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Collection:

Collection ID:CO003556
Collection Summary:Plasma metabolomics samples were prepared from whole blood mixed with EDTA to 10 mM final concentration. To separate plasma, blood samples were centrifuged at 2,000 g and 4 °C for 10 min. Then, 50 µl of plasma were mixed with 450 µl of 100% methanol to reach 90% final methanol concentration. Tissue metabolite extracts were prepared from ~50 mg snap-frozen tissue samples. Each sample was weighed while frozen. Frozen samples were ground at the temperature of liquid nitrogen by Retch Cryomill. Then, 80% methanol was added to each tube at a ratio of 1 ml per 50 mg of tissue. Regardless of the type of metabolite extracts, all samples were centrifuged at 18,000 g and 4 °C for 20 min. The supernatant was then transferred to new Eppendorf tubes and centrifuged again with the same parameters. After centrifugation, the extracts were transferred to glass LC-MS vials.
Collection Protocol Filename:DM_metabolomics_samples.txt
Sample Type:Brain, Heart, Liver, Blood(plasma)
Collection Method:80% methanol extraction for organs, 90% for plasma
Storage Conditions:-80℃
Collection Vials:1.5 ml plastic centrifuge tubes
Storage Vials:1.5 ml plastic centrifuge tubes

Treatment:

Treatment ID:TR003572
Treatment Summary:Cells were grown in RPMI-1640 supplemented with 10% dialyzed FBS and treated with various concentrations of dimethylmalonate (DMM) for 24 h.
Treatment Compound:Fasnall (1-benzyl-N-{5,6-dimethylthieno[2,3-d]pyrimidin-4-yl}pyrrolidin-3-amine, Enamine EN300-14327544)
Treatment Vehicle:1:1 DMSO:PBS

Sample Preparation:

Sampleprep ID:SP003570
Sampleprep Summary:Plasma metabolomics samples were prepared from whole blood mixed with EDTA to 10 mM final concentration. To separate plasma, blood samples were centrifuged at 2,000 g and 4 °C for 10 min. Then, 50 µl of plasma were mixed with 450 µl of 100% methanol to reach 90% final methanol concentration. Tissue metabolite extracts were prepared from ~50 mg snap-frozen tissue samples. Each sample was weighed while frozen. Frozen samples were ground at the temperature of liquid nitrogen by Retch Cryomill. Then, 80% methanol was added to each tube at a ratio of 1 ml per 50 mg of tissue. Regardless of the type of metabolite extracts, all samples were centrifuged at 18,000 g and 4 °C for 20 min. The supernatant was then transferred to new Eppendorf tubes and centrifuged again with the same parameters. After centrifugation, the extracts were transferred to glass LC-MS vials.
Sampleprep Protocol Filename:DM_metabolomics_samples.txt
Processing Storage Conditions:4℃
Extraction Method:80% methanol for organs, 90% for plasma
Extract Enrichment:None
Extract Cleanup:None
Extract Storage:-80℃
Sample Resuspension:None
Sample Derivatization:None
Sample Spiking:None
Subcellular Location:Intracellular metabolites and medium metabolites

Combined analysis:

Analysis ID AN005645 AN005646
Analysis type MS MS
Chromatography type HILIC HILIC
Chromatography system Shimadzu 20AD Shimadzu 20AD
Column Merck SeQuant ZIC-HILIC (150 x 2.1mm,5um) Merck SeQuant ZIC-HILIC (150 x 2.1mm,5um)
MS Type ESI ESI
MS instrument type Triple quadrupole Triple quadrupole
MS instrument name ABI Sciex 5500 QTrap ABI Sciex 5500 QTrap
Ion Mode NEGATIVE POSITIVE
Units Counts per second (cps) Counts per second (cps)

Chromatography:

Chromatography ID:CH004285
Instrument Name:Shimadzu 20AD
Column Name:Merck SeQuant ZIC-HILIC (150 x 2.1mm,5um)
Column Pressure:900-3000 psi
Column Temperature:40
Flow Gradient:0-12.5 min, 80-30% B; 12.5-15 min, 30% B; 15-15.2 min, 30-80% B; 15.2-22.5 min, 80% B
Flow Rate:0-20 min, 0.2 ml/min; 20-21 min 0.2-0.3 ml/min; 21-22 min, 0.3 ml/min; 22-22.1 min, 0.2 ml/min; 22.1-22.5 min, 0.2 ml/min
Injection Temperature:4
Sample Injection:1-5 ul
Solvent A:100% Water; 0.01% ammonium hydroxide; 20 mM ammonium bicarbonate
Solvent B:100% Acetonitrile
Chromatography Type:HILIC

MS:

MS ID:MS005369
Analysis ID:AN005645
Instrument Name:ABI Sciex 5500 QTrap
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:Data were analyzed with SCIEX Multiquant 3.0.3.
Ion Mode:NEGATIVE
Capillary Temperature:500 °C
Capillary Voltage:-4500
Dry Gas Flow:70
Dry Gas Temp:500 °C
Ion Source Temperature:500 °C
Ion Spray Voltage:-4500
Mass Accuracy:UNIT
Source Temperature:500 °C
Spray Voltage:-4500
Desolvation Gas Flow:70
Desolvation Temperature:500 °C
  
MS ID:MS005370
Analysis ID:AN005646
Instrument Name:ABI Sciex 5500 QTrap
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:Data were analyzed with SCIEX Multiquant 3.0.3.
Ion Mode:POSITIVE
Capillary Temperature:500 °C
Capillary Voltage:4500
Dry Gas Flow:70
Dry Gas Temp:500 °C
Ion Source Temperature:500 °C
Ion Spray Voltage:4500
Mass Accuracy:UNIT
Source Temperature:500 °C
Spray Voltage:4500
Desolvation Gas Flow:70
Desolvation Temperature:500 °C
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