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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory
Laurie B Schenkel1, Jennifer R Molina2, Kerren K Swinger3
1Department of Molecular Discovery, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA; MOMA Therapeutics, Cambridge, MA 02142, USA.
Abstract:
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.
Insights
A new chemical probe, RBN012759, effectively inhibits PARP14, a protein promoting tumor growth. This discovery opens avenues for developing PARP14 inhibitors as a novel cancer therapy.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Poly (ADP-ribose) polymerase 14 (PARP14) is implicated in promoting protumor macrophage polarization.
- PARP14 modulates interleukin-4 (IL-4) and interferon-γ signaling, suppressing antitumor inflammatory responses.
Purpose of the Study:
- To discover a potent and selective PARP14 chemical probe for biological studies.
- To investigate the role of PARP14 in tumor immunity and its therapeutic potential.
Main Methods:
- Structure-based drug design was employed to identify PARP14 inhibitors.
- Biochemical assays were used to determine inhibitor potency and selectivity.
- In vitro and in vivo studies assessed the probe's effect on macrophage polarization and tumor gene expression.
Main Results:
- RBN012759 was identified as a potent PARP14 inhibitor (IC50 = 0.003 μM) with >300-fold selectivity over other PARP family members.
- Inhibition of PARP14 by RBN012759 reversed IL-4-driven protumor gene expression in macrophages.
- RBN012759 induced an inflammatory mRNA signature in human tumor explants, similar to immune checkpoint inhibitor therapy.
Conclusions:
- PARP14 plays an immune-suppressive role in the tumor microenvironment.
- PARP14 inhibitors, like RBN012759, show potential as a novel cancer treatment strategy.
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