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

José Luis Marín-Rubio, Rachel E. Peltier-Heap, Maria Emilia Dueñas, Tiaan Heunis, Abeer Dannoura, Joseph Inns, Jonathan Scott, A. John Simpson, Helen J. Blair, Olaf Heidenreich, James M. Allan, Jessica E. Watt, Mathew P. Martin, Barbara Saxty, Matthias Trost

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)12014-12030
Aantal pagina's17
TijdschriftJournal of Medicinal Chemistry
Volume65
Nummer van het tijdschrift18
DOI's
StatusGepubliceerd - 22 sep. 2022
Extern gepubliceerdJa

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