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Confirmation of ZAK as covalent target of Ibrutinib

ABSTRACT: The goal of this experiment was the confirmation of ZAK as a covalent target of Ibrutinib by an affinity enrichment experiment with a linkable analogue of Ibrutinib.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell

SUBMITTER: Maria Faelth Savitski

LAB HEAD: Marcus Bantscheff

PROVIDER: PXD007638 | Pride | 2017-10-13

REPOSITORIES: pride

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			Action	DRS
	04776_F1_R1_P0103248A01_TMT10.raw.gz	Raw
	04776_F1_R1_P0103252A01_TMT10.raw.gz	Raw
	F228283.dat	Other
	F228289.dat	Other

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Publications

Differential Kinobeads Profiling for Target Identification of Irreversible Kinase Inhibitors.

Dittus Lars L Werner Thilo T Muelbaier Marcel M Bantscheff Marcus M

ACS chemical biology 20170912 10

Chemoproteomics profiling of kinase inhibitors with kinobeads enables the assessment of inhibitor potency and selectivity for endogenously expressed protein kinases in cell lines and tissues. Using a small panel of targeted covalent inhibitors, we demonstrate the importance of measuring covalent target binding in live cells. We present a differential kinobeads profiling strategy for covalent kinase inhibitors where a compound is added either to live cells or to a cell extract that enables the co ...[more]

PMID: 28876896

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Identification of the covalent binding site of Ibrutinib and 5Z-7-Oxozeaenol to ZAK

Project description:The goal of this experiment was to identify the reaction site of Ibrutinib and 5Z-7-Oxozeaenol to ZAK by determination of mass shifts according to a covalent modification by the inhibitors using mass spectrometry.

2017-10-13 | PXD007752 | Pride

Ibrutinib induces a global chromatin reorganisation in chronic lymphocytic leukaemia

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Proteoform-level drug target landscapes demonstrates a wider spectrum of ibrutinib targets

Project description:In this study, we investigated the target landscape of the drug ibrutinib using thermal proteome profiling (TPP) and proteoform detection. Our findings demonstrated that ibrutinib interacts with multiple proteoforms, beyond its known targets. Specifically, we identified interactions related to immunomodulation, Golgi trafficking, endosomal trafficking, and glycosylation. These insights shed light on the clinical off-target effects and adverse events associated with ibrutinib. Moreover, our study emphasizes the significance of studyin drug interactions at the proteoform level and its potential implications for precision medicine.

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Project description:Ibrutinib,a novel Bruton'styrosine kinase inhibitor, demonstrated high response rates in B-cell lymphomas but a growing number of ibrutinib treated patients relapse with resistance, fulminant progression and accelerated mortality. Using chemical proteomics and a high-throughput ex vivo assay in a reconstructed tumor microenvironment (TME), we determined the molecular basis for ibrutinib activity and mechanism of acquired ibrutinib resistance. Reciprocal activation of PI3K-AKT-mTOR and integrin β1 signaling were identified as a signaling hub of kinome for ibrutinib resistance, resulting in enforced TME-lymphoma interactions, promoting mantle cell lymphoma (MCL) growth and drug resistance. Combinatorial disruption of BCR signaling and ibrutinib resistance associated pathways led to release of MCL cells from TME, reversal of drugresistance and enhanced anti-MCL activity in murine and patient-derived xenograft models. This study integrated TME-mediated de-novo and acquired drug resistance mechanisms and provides the rationale for novel combination therapeutic strategy against MCL and other B cell malignancies.

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Project description:We performed a high-throughput droplet-based single-cell RNA sequencing experiment on a sensitive MCL cell line model (REC-1) treated with ibrutinib over time using the 10x Genomics platform. Two biological replicates were generated of an untreated control, 6 h, and 48 h ibrutinib-treated cells.

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EGR1-mediated ibrutinib resistance

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Gene expression profiles of ibrutinib-responsive and ibrutinib non-responsive cells in ERBB4 expressing cancer cell lines

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