Abstract DDT02-01: RBN-2397: A first-in-class PARP7 inhibitor targeting a newly discovered cancer vulnerability in stress-signaling pathways

Autor: Patricia E. Rao, Danielle J. Blackwell, Ryan Abo, Kaiko Kunii, Kristy Kuplast-Barr, W. David Church, Victoria M. Richon, Heike Keilhack, Melissa M. Vasbinder, Jan-Rung Mo, Luke Utley, Ellen Bamberg, Mario Niepel, Zacharenia A. Varsamis, Yue Ren, Alvin Lu, Timothy J. Mitchison, Tim J. Wigle, Christina R. Majer, Kevin Wayne Kuntz, Jeff Song, Kerren Kalai Swinger, Joseph M. Gozgit, Bin Gui, Sunaina P. Nayak
Rok vydání: 2020
Předmět:
Zdroj: Cancer Research. 80:DDT02-01
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2020-ddt02-01
Popis: RBN-2397: A first-in-class PARP7 inhibitor targeting a newly discovered cancer vulnerability in stress-signaling pathways PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function (MARylation). PARP7 expression is increased by cellular stresses, including aromatic hydrocarbons and the PARP7 gene is amplified in cancers, especially in those of the upper aerodigestive tract. PARP7 has also been reported to negatively regulate the Type I interferon (IFN) response by interacting with TBK1 during viral infection. As part of our drug discovery efforts to identify inhibitors of PARP7, we utilized structure-based drug design to optimize an unselective monoPARP inhibitor identified by screening Ribon's internal compound collection of PARP inhibitors. Further optimization of potency and physicochemical properties led to the discovery of RBN-2397, a potent and selective small molecule inhibitor of PARP7 catalytic function. A co-crystal structure of RBN-2397 demonstrated binding of the compound in the NAD+-binding pocket. Binding to cellular PARP7 is demonstrated by the ability of RBN-2397 to displace an active site probe in a NanoBRET assay. Functionally, RBN-2397 leads to the inhibition of MARylation of multiple intracellular proteins in PARP7-overexpressing SK-MES-1 cells. We identified a subset of cancers exhibiting dependency on PARP7 for proliferation. Cell lines with higher baseline expression of interferon stimulated genes are more sensitive to RBN-2397 in proliferation assays. We further show that inhibition of PARP7 by RBN-2397 restores Type I IFN signaling as demonstrated by the induction of STAT1 phosphorylation and upregulation of genes enriched for Type I IFN signaling in NCI-H1373 lung cancer cells. Oral dosing of RBN-2397 results in durable, complete tumor regression in a NCI-H1373 lung cancer xenograft and induces tumor-specific adaptive immune memory in an immunocompetent mouse cancer model that is dependent on tumor-derived Type I IFN signaling. Herein, we describe the discovery of the small molecule PARP7 inhibitor RBN-2397, the first therapeutic agent targeting PARP7 to enter clinical trials, and the first disclosure of the inhibitor. We demonstrate PARP7 is a novel therapeutic target and inhibition of PARP7 by RBN-2397 induces both cancer cell autonomous and immune stimulatory effects via enhanced IFN signaling. Citation Format: Melissa M. Vasbinder, Joseph M. Gozgit, Ryan P. Abo, Kaiko Kunii, Kristy G. Kuplast-Barr, Bin Gui, Alvin Z. Lu, Kerren K. Swinger, Tim J. Wigle, Danielle J. Blackwell, Christina R. Majer, Yue Ren, Mario Niepel, Zacharenia A. Varsamis, Sunaina P. Nayak, Ellen Bamberg, Jan-Rung Mo, W David Church, Jeff Song, Luke Utley, Patricia E. Rao, Timothy J. Mitchison, Kevin W. Kuntz, Victoria M. Richon, Heike Keilhack. RBN-2397: A first-in-class PARP7 inhibitor targeting a newly discovered cancer vulnerability in stress-signaling pathways [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr DDT02-01.
Databáze: OpenAIRE
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