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PXD035201

PXD035201 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleChemical proteomics with novel fully functionalized fragments and stringent target prioritization identifies the glutathione-dependent isomerase GSTZ1 as a lung cancer target
DescriptionPhotoreactive fragment-like probes have been applied to discover target proteins that constitute novel cellular vulnerabilities and to identify viable chemical hits for drug discovery. Through forming covalent bonds, functionalized probes can achieve stronger target engagement and require less effort for on-target mechanism validation. However, the design of probe libraries, which directly affects the biological target space that is interrogated, and effective target prioritization remain critical challenges of such a chemical proteomic platform. In this study, we designed and synthesized a diverse panel of twenty fragment-based probes with privileged structural motifs containing both natural product and lead-like elements. These probes were fully functionalized with orthogonal diazirine and alkyne moieties and used for protein crosslinking in live lung cancer cells, target enrichment via “click chemistry,” and subsequent target identification through label-free quantitative LC-MS/MS analysis. Pair-wise comparison with a blunted negative control probe and stringent prioritization via individual cross-comparisons against the entire panel identified glutathione S-transferase zeta 1 (GSTZ1) as a specific and unique target candidate. DepMap database query, RNA interference-based gene silencing and proteome-wide tyrosine reactivity profiling suggested that GSTZ1 cooperated with different oncogenic alterations by supporting survival signaling in refractory NSCLC cells. This finding may form the basis for developing novel GSTZ1 inhibitors to improve the therapeutic efficacy of oncogene-directed targeted drugs. In summary, we designed a novel fragment-based probe panel and developed a target prioritization scheme with improved stringency, which allows for identification of unique target candidates, such as GSTZ1 in refractory lung cancer.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_06:35:14.538.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD035201
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterJohn Koomen
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListbiotinylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-07-09 09:06:10ID requested
12024-04-05 10:02:03announced
22024-10-22 06:35:15announced2024-10-22: Updated project metadata.
Publication List
Liao Y, Chin Chan S, Welsh EA, Fang B, Sun L, Sch, ö, nbrunn E, Koomen JM, Duckett DR, Haura EB, Monastyrskyi A, Rix U, Chemical Proteomics with Novel Fully Functionalized Fragments and Stringent Target Prioritization Identifies the Glutathione-Dependent Isomerase GSTZ1 as a Lung Cancer Target. ACS Chem Biol, 18(2):251-264(2023) [pubmed]
10.6019/PXD035201;
10.1021/acschembio.2c00587;
Keyword List
submitter keyword: Photoreactive Probes,Lung Cancer, GSTZ1, Chemical Proteomics
Contact List
Uwe Rix, PhD
contact affiliationDrug Discovery Moffitt Cancer Center Tampa, FL, USA
contact emailuwe.rix@moffitt.org
lab head
John Koomen
contact affiliationMoffitt Cancer Center
contact emailjohn.koomen@moffitt.org
dataset submitter
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Dataset FTP location
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