Targeting PARP7: The Development and Impact of RBN-2397 in Cancer Therapy

RBN-2397 is a novel and selective inhibitor of the enzyme PARP7, which is implicated in cancer cell growth and immune response regulation. This monoPARP facilitates the MARylation process by transferring ADP-ribose to target proteins, a function that is upregulated under stress conditions and observed in various cancers, notably those affecting the upper aerodigestive tract. The development of RBN-2397 was driven by structure-based drug design, enhancing the potency and properties of an initial unselective inhibitor from Ribon's library. The compound's binding to PARP7 is confirmed through a co-crystal structure, showing its interaction with the NAD+-binding site. RBN-2397's efficacy is demonstrated by its ability to inhibit MARylation in cells with elevated PARP7 expression and to sensitize cells with high interferon-stimulated gene expression to its effects.

Furthermore, the drug was found to reactivate Type I interferon signaling pathways by inducing STAT1 phosphorylation and increasing the expression of interferon-related genes in lung cancer cells. In vivo studies revealed that oral administration of RBN-2397 led to complete tumor regression in a lung cancer model and promoted an adaptive immune response reliant on tumor-derived Type I interferon signaling.

The research highlights the potential of PARP7 as a therapeutic target and introduces RBN-2397 as the first inhibitor of this enzyme to be considered for clinical trials. The findings underscore the dual role of RBN-2397 in directly targeting cancer cells and stimulating the immune system through enhanced interferon signaling. The study was presented at the 2020 Annual Meeting of the American Association for Cancer Research by Melissa M. Vasbinder and colleagues.