All Publications

  • ENPP1's regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling. Proceedings of the National Academy of Sciences of the United States of America Carozza, J. A., Cordova, A. F., Brown, J. A., AlSaif, Y., Bohnert, V., Cao, X., Mardjuki, R. E., Skariah, G., Fernandez, D., Li, L. 2022; 119 (21): e2119189119


    SignificanceThe immune system strikes a careful balance between launching a robust response to threats and avoiding overactivation. The molecule cGAMP is an immunotransmitter that activates innate immunity and signals extracellularly, where it is subject to degradation by the enzyme ENPP1. Here, we engineer ENPP1 to lose activity toward cGAMP but not other substrates, thus creating a biochemically precise tool to understand how ENPP1 regulates extracellular cGAMP and thus innate immunity. We uncover that ENPP1's degradation of extracellular cGAMP has a long evolutionary history, and that this mechanism is critical for controlling diverse immune threats, including viral infection and inflammation.

    View details for DOI 10.1073/pnas.2119189119

    View details for PubMedID 35588451

  • Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP. Cell chemical biology Carozza, J. A., Brown, J. A., Bohnert, V., Fernandez, D., AlSaif, Y., Mardjuki, R. E., Smith, M., Li, L. 2020


    Cancer cells initiate an innate immune response by synthesizing and exporting the small-molecule immunotransmitter cGAMP, which activates the anti-cancer Stimulator of Interferon Genes (STING) pathway in the host. An extracellular enzyme, ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), hydrolyzes cGAMP and negatively regulates this anti-cancer immune response. Small-molecule ENPP1 inhibitors are much needed as tools to study the basic biology of extracellular cGAMP and as investigational cancer immunotherapy drugs. Here, we surveyed structure-activity relationships around a series of cell-impermeable and thus extracellular-targeting phosphonate inhibitors of ENPP1. In addition, we solved the crystal structure of an exemplary phosphonate inhibitor to elucidate the interactions that drive potency. This study yielded several best-in-class inhibitors with Ki< 2nM and excellent physicochemical and pharmacokinetic properties. Finally, we demonstrate that an ENPP1 inhibitor delays tumor growth in a breast cancer mouse model. Together, we have developed ENPP1 inhibitors that are excellent tool compounds and potential therapeutics.

    View details for DOI 10.1016/j.chembiol.2020.07.007

    View details for PubMedID 32726585