2. Academic Validation
  3. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis

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

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.

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