A MALDI-TOF assay identifies nilotinib as an inhibitor of inflammation in acute myeloid leukaemia

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 tracking 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 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) using TMTpro 16plex. Unlike imatinib, nilotinib inhibits p38-alpha (MAPK14) signalling. This inhibition 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 contribute to the treatment of inflammation in myeloid neoplasms and other diseases.

Advances in high‐throughput mass spectrometry in drug discovery

“…In another study, a label‐free cellular phenotypic drug discovery assay was developed to identify anti‐inflammatory drugs in human monocytes derived from acute myeloid leukaemia. The screen identified that the inhibitor nilotinib blocked LPS‐induced inflammatory responses (preprint: Marín‐Rubio et al , 2021 ).…”