A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants. Issue 8 (19th August 2021)

• Record Type: Journal Article
• Authors: Schenkel, Laurie B.; Molina, Jennifer R.; Swinger, Kerren K.; Abo, Ryan; Blackwell, Danielle J.; Lu, Alvin Z.; Cheung, Anne E.; Church, W. David; Kunii, Kaiko; Kuplast-Barr, Kristy G.; Majer, Christina R.; Minissale, Elena; Mo, Jan-Rung; Niepel, Mario; Reik, Christopher; Ren, Yue; Vasbinder, Melissa M.; Wigle, Tim J.; Richon, Victoria M.; Keilhack, Heike; Kuntz, Kevin W.
• Is Part Of: Cell chemical biology. Volume 28:Issue 8(2021)
• Page Start: 1158
• Page End: 1168.e13
• Publication Date: 2021-08-19
• Subjects: poly(ADP-ribose) polymerase 14 (PARP14) -- chemical probe -- monoPARP -- macrophage polarization -- immuno-oncology -- immunosuppression -- PARP14 inhibitor; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2021.02.010
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: PARP14 has been implicated by genetic knockout studies to promote protumor macrophage polarization and suppress the antitumor inflammatory response due to its role in modulating interleukin-4 (IL-4) and interferon-γ signaling pathways. Here, we describe structure-based design efforts leading to the discovery of a potent and highly selective PARP14 chemical probe. RBN012759 inhibits PARP14 with a biochemical half-maximal inhibitory concentration of 0.003 μM, exhibits >300-fold selectivity over all PARP family members, and its profile enables further study of PARP14 biology and disease association both in vitro and in vivo . Inhibition of PARP14 with RBN012759 reverses IL-4-driven protumor gene expression in macrophages and induces an inflammatory mRNA signature similar to that induced by immune checkpoint inhibitor therapy in primary human tumor explants. These data support an immune suppressive role of PARP14 in tumors and suggest potential utility of PARP14 inhibitors in the treatment of cancer. Graphical abstract: Highlights: The first highly potent and selective inhibitor of PARP14, RBN012759, is described The profile of RBN012759 enables its use as an in vitro and in vivo chemical probe RBN012759 reversed IL-4-driven protumor gene expression An inflammatory gene signature was activated with RBN012759 treatment Abstract : Schenkel et al. disclose the first highly potent and selective inhibitor of PARP14, RBN012759, an in vitro and in vivo chemical probe. RBN012759 reverses IL-4-driven protumor gene expression in macrophages and induces an inflammatory mRNA signature in primary human tumor explants, suggesting utility of PARP14 inhibitors for treating cancer.