Proteomics

Dataset Information

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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


ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Type Ii Pneumocyte

DISEASE(S): Lung Adenocarcinoma

SUBMITTER: John Koomen  

LAB HEAD: Uwe Rix, PhD

PROVIDER: PXD037894 | Pride | 2024-04-05

REPOSITORIES: Pride

Dataset's files

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F003492.dat Other
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Publications

Chemical Proteomics with Novel Fully Functionalized Fragments and Stringent Target Prioritization Identifies the Glutathione-Dependent Isomerase GSTZ1 as a Lung Cancer Target.

Liao Yi Y   Chin Chan Sean S   Welsh Eric A EA   Fang Bin B   Sun Luxin L   Schönbrunn Ernst E   Koomen John M JM   Duckett Derek R DR   Haura Eric B EB   Monastyrskyi Andrii A   Rix Uwe U  

ACS chemical biology 20230111 2


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 critic  ...[more]

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