PXD037894

PXD037894 is an original dataset announced via ProteomeXchange.

Title	Chemical proteomics with novel fully functionalized fragments and stringent target prioritization identifies the glutathione-dependent isomerase GSTZ1 as a lung cancer target: SuTEx of GSTZ1 KD
Description	Photoreactive 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 containing natural product-based privileged structural motifs for small-molecule lead discovery. 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 the identification of unique target candidates, such as GSTZ1 in refractory lung cancer.
HostingRepository	PRIDE
AnnounceDate	2024-04-05
AnnouncementXML	Submission_2024-04-05_09:35:18.985.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD037894
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-03 04:06:11	ID requested
⏵ 1	2024-04-05 09:35:19	announced

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/PXD037894;

10.1021/acschembio.2c00587;

submitter keyword: fragment-based drug discovery, GSTZ1,Lung cancer, chemical proteomics

Uwe Rix, PhD
contact affiliation	Moffitt Cancer Center Tampa, FL, USA
contact email	uwe.rix@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/04/PXD037894

PRIDE project URI

• PRIDE
  1. PXD037894
     1. Label: PRIDE project
     2. Name: Chemical proteomics with novel fully functionalized fragments and stringent target prioritization identifies the glutathione-dependent isomerase GSTZ1 as a lung cancer target: SuTEx of GSTZ1 KD