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CellEKT: A chemical proteomics assay to profile cellular target engagement of kinase inhibitors

ABSTRACT: Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44 is a chemical probe based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44 binding, which can be interpreted as in situ target engagement. Here, a workflow is presented which is optimized for kinome coverage, reproducibility and data processing. This dataset pertains to the difference in kinome coverage when using different protocols and (strept)avidin beads.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Joel Rüegger

LAB HEAD: Mario van

PROVIDER: PXD035542 | Pride | 2025-04-08

REPOSITORIES: Pride

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			Action	DRS
	Avidin_new_01.raw	Raw
	Avidin_new_02.raw	Raw
	Avidin_new_03.raw	Raw
	Avidin_old_01.raw	Raw
	Avidin_old_02.raw	Raw

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Similar Datasets

CellEKT: A chemical proteomics assay to profile cellular target engagement of kinase inhibitors

Project description:Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44 is a chemical probe based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44 binding, which can be interpreted as in situ target engagement. Here, a workflow is presented which is optimized for kinome coverage, reproducibility and data processing. This dataset pertains to the kinome coverage of XO44 in 19 human cell lines as determined by chemical proteomics.

2025-04-08 | PXD035544 | Pride

CellEKT: A chemical proteomics assay to profile cellular target engagement of kinase inhibitors

Project description:Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44, ALX005 and ALX011 are chemical probes based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44/ALX005/ALX011 binding, which can be interpreted as in situ target engagement. Here CellEKT is presented, a workflow which is optimized for kinome coverage, reproducibility and data processing. This dataset contains the kinome coverage assessment of ALX005 and ALX011 in comparison to the kinome coverage of XO44 which was determined in the selectivity screening of Midostaurin (PXD035619, PXD035549)

2025-04-08 | PXD054026 | Pride

CellEKT: A chemical proteomics assay to profile cellular target engagement of kinase inhibitors

Project description:Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44 is a chemical probe based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44 binding, which can be interpreted as in situ target engagement. Here, a workflow is presented which is optimized for kinome coverage, reproducibility and automated data processing. This dataset pertains to the use of high probe dose samples as peptide library in MaxQuant.

2025-04-08 | PXD035540 | Pride

CellEKT: A chemical proteomics assay to profile cellular target engagement of kinase inhibitors

Project description:Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44, ALX005 and ALX011 are chemical probes based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44/ALX005/ALX011 binding, which can be interpreted as in situ target engagement. Here CellEKT is presented, a workflow which is optimized for kinome coverage, reproducibility and data processing. This dataset pertains to the selectivity testing of Dasatinib in MV4-11 cells using a probe cocktail of XO44, ALX005 and ALX011.

2025-04-08 | PXD053911 | Pride

CellEKT: A chemical proteomics assay to profile cellular target engagement of kinase inhibitors

Project description:Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44 is a chemical probe based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44 binding, which can be interpreted as in situ target engagement. Here, a workflow is presented which is optimized for kinome coverage, reproducibility and data processing. This dataset pertains to the selectivity testing of Midostaurin in MV4-11 cells.

2025-04-08 | PXD035549 | Pride

CellEKT: A chemical proteomics assay to profile cellular target engagement of kinase inhibitors

Project description:Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44 is a chemical probe based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44 binding, which can be interpreted as in situ target engagement. Here, a workflow is presented which is optimized for kinome coverage, reproducibility and data processing. This dataset pertains to the selectivity testing of Midostaurin in HEK293T cells.

2025-04-08 | PXD035619 | Pride

CellEKT: A chemical proteomics assay to profile cellular target engagement of kinase inhibitors

Project description:Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44 is a chemical probe based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44 binding, which can be interpreted as in situ target engagement. Here, a workflow is presented which is optimized for kinome coverage, reproducibility and data processing. This dataset pertains to the selectivity testing of BTK inhibitors in MV4-11 cells.

2025-04-08 | PXD035550 | Pride

CellEKT: A chemical proteomics assay to profile cellular target engagement of kinase inhibitors

Project description:Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44 is a chemical probe based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44 binding, which can be interpreted as in situ target engagement. Here, a workflow is presented which is optimized for kinome coverage, reproducibility and data processing. This dataset pertains to the selectivity testing of BTK inhibitors in HEK293T cells.

2025-04-08 | PXD035551 | Pride

Establishing an activity-based protein profiling platform to screen in situ kinase inhibitor engagement

Project description:Activity-based protein profiling is a powerful tool to study target engagement in complex biological environments. XO44 is a chemical probe based on the scaffold of a promiscuous kinase binder, which covalently reacts with a conserved lysine in the ATP-binding pocket of kinases. Pretreatment of cells with a drug (candidate) results in competition of XO44 binding, which can be interpreted as in situ target engagement. Here, a workflow is presented which is optimized for kinome coverage, reproducibility and data processing. This dataset pertains to the selectivity testing of Midostaurin in MV4-11 cells. (Phosphoproteomics)

2025-04-09 | PXD055387 | Pride

Chemical proteomics with novel fully functionalized fragments and stringent target prioritization identifies the glutathione-dependent isomerase GSTZ1 as a lung cancer target

Project 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 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.

2024-04-05 | PXD035201 | Pride

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