Poly (ADP-ribose) polymerase (PARP) is a family of proteins that participate in many cellular processes, such as DNA repair, genome stability, and programmed cell death. The overactivation of PARP leads to the depletion of the NAD+pool of cells, resulting in ATP deficiency, energy loss, and subsequent cell death. Meanwhile, PARP activation plays a key role in mediating photoreceptor apoptosis not only in the MNU model but also in the mouse model of hereditary retinal degeneration. Nonetheless, PARP regulates transcription by interacting with transcription factors, such as NF- κ B and AP-1. Besides, PARP14 uses nicotinamide adenine dinucleotide (NAD+) as a metabolic substrate to modify the target protein by mono-ADP-ribosylation and participates in the cellular response and signal pathway of the immune system. Moreover, PARP14 can modify the single ADP ribosylation on the target protein, thus triggering a cell reaction.

Furthermore, PARP14 promotes the anti-inflammatory IL-4-mediated signal pathway by activating STAT6-dependent gene expression and inhibiting STAT-1 dependent gene expression. The ability of PARP14 to regulate the IL-4 signaling pathway is related to many diseases. Importantly, PARP14 participates in normal immune function through the IL-4 signal pathway and is a survival-promoting factor for multiple myeloma and hepatocellular carcinoma. Therefore, PARP14 is considered an attractive target for the treatment of tumors and allergic inflammation. More importantly, based on the synthetic lethal theory and its unique role in the repair of homologous recombinant DNA, PARP14 may become a potential target of chemical sensitizers. Here, we will introduce a selective PARP14inhibitor, RBN-3143.

RBN-3143 is a Selective PARP14 Inhibitor for Lung Inflammation Research.

First of all, RBN-3143 is a potent and selective PARP14 inhibitor with an IC₅₀ value of 4 nM. RBN-3143 is an NAD+-competitive catalytic inhibitor of PARP14. Particularly, RBN-3143 inhibits PARP14-mediated ADP-ribosylation and stabilizes PARP14 in cell lines. Interestingly, RBN-3143 has the potential for lung inflammation research.

In the second place, RBN-3143 with 5 μg by intranasal administration can improve steroid-resistant asthma mouse models. Obviously, RBN-3143 suppressed the accumulation of alarmins TSLP, IL-33, and IL-25. RBN-3143 is well-tolerated in preclinical studies.

All in all, RBN-3143 is a potent and selective PARP14 inhibitor for lung inflammation research.

References:

[1] Niepel M, et, al. European Respiratory Journal 2022 60: 4642.