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Lookup NU author(s): Dr Jose Luis Marin-RubioORCiD, Dr Maria Duenas FadicORCiD, Dr Tiaan Heunis, Dr Abeer Dannoura, Dr Joe Inns, Jonathan Scott, Professor John SimpsonORCiD, Dr Helen Blair, Professor Olaf Heidenreich, Professor James Allan, Dr Jessica WattORCiD, Dr Mathew Martin, Professor Matthias TrostORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 Authors. 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 inhibitor nilotinib, but not the structurally similar imatinib, blocks inflammatory responses. In order to identify the cellular (off-)targets of nilotinib, we performed thermal proteome profiling (TPP). Unlike imatinib, nilotinib and other later-generation BCR-ABL inhibitors bind to p38α and inhibit the p38α-MK2/3 signaling axis, which suppressed pro-inflammatory cytokine expression, cell adhesion, and innate immunity markers in activated monocytes derived from AML. Thus, our study provides a tool for the discovery of new anti-inflammatory drugs, which could contribute to the treatment of inflammation in myeloid neoplasms and other diseases.
Author(s): Marin-Rubio JL, Peltier-Heap RE, Duenas ME, Heunis T, Dannoura A, Inns J, Scott J, Simpson AJ, Blair HJ, Heidenreich O, Allan JM, Watt JE, Martin MP, Saxty B, Trost M
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Year: 2022
Volume: 65
Issue: 18
Pages: 12014-12030
Print publication date: 22/09/2022
Online publication date: 12/09/2022
Acceptance date: 02/04/2018
Date deposited: 13/10/2022
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
URL: https://doi.org/10.1021/acs.jmedchem.2c00671
DOI: 10.1021/acs.jmedchem.2c00671
PubMed id: 36094045
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