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

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

  • J Med Chem. 2022 Sep 22;65(18):12014-12030. doi: 10.1021/acs.jmedchem.2c00671.
José Luis Marín-Rubio 1,  Rachel E Peltier-Heap 1,  Maria Emilia Dueñas 1,  Tiaan Heunis 1 2,  Abeer Dannoura 1,  Joseph Inns 1,  Jonathan Scott 3,  A John Simpson 3 4,  Helen J Blair 5,  Olaf Heidenreich 5,  James M Allan 5,  Jessica E Watt 6,  Mathew P Martin 6,  Barbara Saxty 7,  Matthias Trost 1
Affiliations

Affiliations

  • 1 Laboratory for Biological Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.
  • 2 Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
  • 3 Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.
  • 4 Respiratory Medicine Unit, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.
  • 5 Translational and Clinical Research Institute, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, UK.
  • 6 Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
  • 7 LifeArc, SBC Open Innovation Campus, Stevenage SG1 2FX, UK.
PMID: 36094045 DOI: 10.1021/acs.jmedchem.2c00671
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 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.

Figures