生物
调节器
干扰素
功能(生物学)
先天免疫系统
信号转导
基因
细胞生物学
免疫系统
胚胎干细胞
生物化学
遗传学
作者
Daniel J. Sanderson,Kelsie M Rodriguez,Daniel S. Bejan,Ninni Elise Olafsen,Inga D Bohn,Ana Kojic,Sunil Sundalam,Ivan Rodriguez Siordia,Anna K Duell,Nancy Deng,Carsten Schultz,Denis M. Grant,Jason Matthews,Michael S. Cohen
标识
DOI:10.1016/j.chembiol.2022.11.012
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI