DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis

  • Nat Chem Biol. 2017 Jan;13(1):46-53. doi: 10.1038/nchembio.2229.
Marian C Okondo  1 ,  Darren C Johnson  2 ,  Ramya Sridharan  3 ,  Eun Bin Go  2 ,  Ashley J Chui  2 ,  Mitchell S Wang  3 ,  Sarah E Poplawski  4 ,  Wengen Wu  4 ,  Yuxin Liu  4 ,  Jack H Lai  4 ,  David G Sanford  4 ,  Michael O Arciprete  4 ,  Todd R Golub  5  6  7  8 ,  William W Bachovchin  4  9 ,  Daniel A Bachovchin  1  2  3
Affiliations
  • 1. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 2. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 3. Graduate Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
  • 4. Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
  • 5. The Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
  • 6. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 7. Harvard Medical School, Boston, Massachusetts, USA.
  • 8. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • 9. Arisaph Pharmaceuticals, Boston, Massachusetts, USA.
PMID: 27820798 DOI: 10.1038/nchembio.2229
Abstract

Val-boroPro (Talabostat, PT-100), a nonselective inhibitor of post-proline cleaving serine proteases, stimulates mammalian immune systems through an unknown mechanism of action. Despite this lack of mechanistic understanding, Val-boroPro has attracted substantial interest as a potential Anticancer agent, reaching phase 3 trials in humans. Here we show that Val-boroPro stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and Macrophages known as Pyroptosis. We demonstrate that the inhibition of two serine proteases, DPP8 and DPP9, activates the pro-protein form of Caspase-1 independent of the inflammasome adaptor ASC. Activated pro-caspase-1 does not efficiently process itself or IL-1β but does cleave and activate gasdermin D to induce Pyroptosis. Mice lacking Caspase-1 do not show immune stimulation after treatment with Val-boroPro. Our data identify what is to our knowledge the first small molecule that induces Pyroptosis and reveals a new checkpoint that controls the activation of the innate immune system.