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
  • 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.