6we3 | pdb_00006we3
Human PARP14 (ARTD8), catalytic fragment in complex with compound 3
Structural highlights
FunctionPAR14_HUMAN Enhances STAT6-dependent transcription (By similarity). Has ADP-ribosyltransferase activity. Publication Abstract from PubMedPARP14 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-gamma 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 muM, 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. A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants.,Schenkel LB, Molina JR, Swinger KK, Abo R, Blackwell DJ, Lu AZ, Cheung AE, Church WD, Kunii K, Kuplast-Barr KG, Majer CR, Minissale E, Mo JR, Niepel M, Reik C, Ren Y, Vasbinder MM, Wigle TJ, Richon VM, Keilhack H, Kuntz KW Cell Chem Biol. 2021 Mar 2. pii: S2451-9456(21)00095-7. doi:, 10.1016/j.chembiol.2021.02.010. PMID:33705687[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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