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

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.