A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants

Laurie B Schenkel; Jennifer R Molina; Kerren K Swinger; Ryan Abo; Danielle J Blackwell; Alvin Z Lu; Anne E Cheung; W David Church; Kaiko Kunii; Kristy G Kuplast-Barr; Christina R Majer; Elena Minissale; Jan-Rung Mo; Mario Niepel; Christopher Reik; Yue Ren; Melissa M Vasbinder; Tim J Wigle; Victoria M Richon; Heike Keilhack; Kevin W Kuntz

doi:10.1016/j.chembiol.2021.02.010

A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants

Cell Chem Biol. 2021 Aug 19;28(8):1158-1168.e13. doi: 10.1016/j.chembiol.2021.02.010. Epub 2021 Mar 10.

Authors

Laurie B Schenkel¹, Jennifer R Molina², Kerren K Swinger³, Ryan Abo⁴, Danielle J Blackwell⁵, Alvin Z Lu², Anne E Cheung⁶, W David Church⁵, Kaiko Kunii², Kristy G Kuplast-Barr², Christina R Majer⁵, Elena Minissale², Jan-Rung Mo², Mario Niepel², Christopher Reik⁷, Yue Ren⁵, Melissa M Vasbinder⁵, Tim J Wigle⁵, Victoria M Richon⁸, Heike Keilhack², Kevin W Kuntz⁹

Affiliations

¹ Department of Molecular Discovery, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA; MOMA Therapeutics, Cambridge, MA 02142, USA.
² Department of Biological Sciences, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA.
³ Department of Molecular Discovery, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA; Xilio Therapeutics, Waltham, MA 02451, USA.
⁴ Department of Biological Sciences, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA; Obsidian Therapeutics, Cambridge, MA 02138, USA.
⁵ Department of Molecular Discovery, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA.
⁶ Department of Biological Sciences, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA; A2Empowerment, Arlington, MA 02474, USA.
⁷ Department of Molecular Discovery, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA; Bain & Company, Boston, MA 02116, USA.
⁸ Department of Molecular Discovery, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA; Department of Biological Sciences, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA.
⁹ Department of Molecular Discovery, Ribon Therapeutics, Inc., Cambridge, MA 02140, USA. Electronic address: kkuntz@ribontx.com.

PMID: 33705687
DOI: 10.1016/j.chembiol.2021.02.010

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.

Keywords: PARP14 inhibitor; chemical probe; immuno-oncology; immunosuppression; macrophage polarization; monoPARP; poly(ADP-ribose) polymerase 14 (PARP14).

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Dose-Response Relationship, Drug
Female
Gene Expression Regulation / drug effects
Gene Expression Regulation / genetics
HEK293 Cells
Humans
Inflammation / drug therapy*
Inflammation / genetics
Inflammation / metabolism
Interleukin-4 / antagonists & inhibitors*
Interleukin-4 / genetics
Kidney Neoplasms / drug therapy*
Kidney Neoplasms / genetics
Kidney Neoplasms / metabolism
Macrophages / drug effects*
Macrophages / metabolism
Male
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Poly(ADP-ribose) Polymerases / genetics
Poly(ADP-ribose) Polymerases / metabolism*
RAW 264.7 Cells
RNA, Messenger / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

Antineoplastic Agents
RNA, Messenger
Interleukin-4
PARP14 protein, human
Parp14 protein, mouse
Poly(ADP-ribose) Polymerases