Search

The mono-ADP-ribosyltransferase PARP7 has emerged as a key negative regulator of cytosolic NA-sensors of the innate immune system. We apply a rational design strategy for converting a pan-PARP inhibitor into a potent selective PARP7 inhibitor (KMR-206). Consistent with studies using the structurally distinct PARP7 inhibitor RBN-2397, co-treatment of mouse embryonic fibroblasts with KMR-206 and NA-sensor ligands synergistically induced the expression of the type I interferon, IFN-β. In mouse colon carcinoma (CT-26) cells, KMR-206 alone induced IFN-β. Both KMR-206 and RBN-2397 increased PARP7 protein levels in CT-26 cells, demonstrating that PARP7's catalytic activity regulates its own protein levels. Curiously, treatment with saturating doses of KMR-206 and RBN-2397 achieved different levels of PARP7 protein, which correlated with the magnitude of type I interferon gene expression. These latter results have important implications for the mechanism of action of PARP7 inhibitors and highlights the usefulness of having structurally distinct chemical probes for the same target. [Display omitted] • Structure-based design leads to a highly potent and selective PARP7 inhibitor (KMR-206) • KMR-206 synergizes with AHR ligands to induce CYP1A1 expression • KMR-206 synergizes with NA-sensor ligands to induce IFN-I signaling • The extent of PARP7 inhibitor-mediated IFN-I induction correlates with PARP7 abundance Sanderson et al. describe a potent and selective inhibitor of PARP7. Cellular investigations using this inhibitor confirm PARP7s roles in AHR signaling regulation and type I interferon signaling. This inhibitor will be a useful tool for further studies into PARP7 biology. [ABSTRACT FROM AUTHOR]