Proteomics

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A MALDI-TOF assay identifies nilotinib as an inhibitor of inflammation


ABSTRACT: Inflammatory responses are important in cancer, particularly in the context of monocyte-rich aggressive myeloid neoplasm. We developed a label-free cellular phenotypic drug discovery assay to identify anti-inflammatory drugs in human monocytes derived from acute myeloid leukemia (AML), by quantifying several biological features ionizing from only 2,500 cells using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A proof-of-concept screening showed that the BCR-ABL inhibitor nilotinib, but not the structurally similar imatinib, blocks inflammatory responses in AML and multiple myeloma. In order to identify the cellular (off-)targets for nilotinib, we performed thermal proteome profiling (TPP) over a range of temperatures and compound concentrations. Unlike imatinib, nilotinib inhibits p38 alpha MAP Kinase (MAPK14) and its downstream signaling pathway. This suppressed the expression of inflammatory cytokines, cell adhesion, and innate immunity markers in activated human monocytes derived from AML. Thus, our study provides a tool for the discovery of new anti-inflammatory drugs, which could potentially contribute to the treatment of inflammation in myeloid neoplasms and other diseases.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Monocyte

DISEASE(S): Acute Leukemia,Lymphoma

SUBMITTER: Matthias Trost  

LAB HEAD: Prof. Matthias Trost

PROVIDER: PXD025020 | Pride | 2022-09-30

REPOSITORIES: Pride

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Publications

A Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Assay Identifies Nilotinib as an Inhibitor of Inflammation in Acute Myeloid Leukemia.

Marín-Rubio José Luis JL   Peltier-Heap Rachel E RE   Dueñas Maria Emilia ME   Heunis Tiaan T   Dannoura Abeer A   Inns Joseph J   Scott Jonathan J   Simpson A John AJ   Blair Helen J HJ   Heidenreich Olaf O   Allan James M JM   Watt Jessica E JE   Martin Mathew P MP   Saxty Barbara B   Trost Matthias M  

Journal of medicinal chemistry 20220912 18


Inflammatory responses are important in cancer, particularly in the context of monocyte-rich aggressive myeloid neoplasm. We developed a label-free cellular phenotypic drug discovery assay to identify anti-inflammatory drugs in human monocytes derived from acute myeloid leukemia (AML), by tracking several features ionizing from only 2500 cells using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A proof-of-concept screen showed that the BCR-ABL inhibito  ...[more]

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