1. A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants
- Author
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Tim J. Wigle, Elena Minissale, Alvin Lu, Kristy Kuplast-Barr, W. David Church, Jennifer R. Molina, Heike Keilhack, Kaiko Kunii, Anne Cheung, Yue Ren, Christina R. Majer, Christopher Reik, Kevin Wayne Kuntz, Mario Niepel, Victoria M. Richon, Laurie B. Schenkel, Kerren Kalai Swinger, Jan-Rung Mo, Danielle J. Blackwell, Ryan Abo, and Melissa M. Vasbinder
- Subjects
Male ,Models, Molecular ,Poly ADP ribose polymerase ,Clinical Biochemistry ,Macrophage polarization ,Antineoplastic Agents ,Biology ,Biochemistry ,Mice ,Immune system ,Drug Discovery ,Gene expression ,medicine ,Animals ,Humans ,Macrophage ,RNA, Messenger ,Molecular Biology ,Inflammation ,Pharmacology ,Messenger RNA ,Dose-Response Relationship, Drug ,Molecular Structure ,Macrophages ,Cancer ,medicine.disease ,Kidney Neoplasms ,Mice, Inbred C57BL ,HEK293 Cells ,RAW 264.7 Cells ,Gene Expression Regulation ,Cancer research ,Molecular Medicine ,Female ,Interleukin-4 ,Poly(ADP-ribose) Polymerases ,Signal transduction - 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.
- Published
- 2021