Poly (ADP-ribose) polymerases (PARPs) are a group of enzymes that consist of 17 different members. They can be further classified into poly-adenosine diphosphate ribose polymerases (polyPARP) and mono-(ADP-ribosyl) transferases (monoPARP) based on the pattern of ribosylation of substrates [1], [2], [3]. PARPs play a crucial role in governing essential cellular mechanisms, encompassing the regulation of gene expression, protein degradation, and a myriad of responses to various cellular stresses [4], [5], [6], [7]. PARP7, also known as ARTD14 or TIPARP, is a mono-PARP protein that is composed of 657 amino acids [8], [9], [10]. Studies have shown that PARP7 plays a significant importance in regulating the transcription of various target genes, modulating immune responses, and influencing the repair of brain damage following stroke [11], [12], [13], [14], [15], [16], [17]. A particular aspect of PARP7 that has gained significant attention is its involvement in immune recovery against tumors. In cancer cells, PARP7 modifies TANK-binding kinases 1 (TBK1) through the addition of a solitary ADP-ribose unit. This modification of TBK1, known as mono (ADP-ribosylation), obstructs its process of phosphorylation, consequently impeding type Ⅰ interferon signaling and subsequent immune responses [14], [18], [19].

Hence, the suppression of tumor growth can be achieved by hindering the PARP7 activity in cancer cells, thus restoring the signaling of type Ⅰ interferon (IFN Ⅰ) (Fig. 1) [19], [20]. Collectively, PARP7 is considered a promising target for cancer therapy due to its role in immunomodulation.

Given the significance of inhibiting PAPR7 in cancer therapy, several PARP7 small-molecular inhibitors have been reported. RBN-2397 was the first PARP7 inhibitor reported by Ribon Therapeutics, which demonstrated noteworthy inhibitory activity on PARP1/2/7/12 (37/17/3/25 nM) [19]. The preclinical study demonstrated that it could restore IFN signaling in CT26 cell lines. Additionally, a Phase Ⅰa study (Clinical Trials identifier: NCT04053673) demonstrated that RBN-2397 was well tolerated, displayed proof of inhibiting the target, and presented initial signs of clinical effectiveness [21].

There have been reports on various PARP7 inhibitors derived from the RBN-2397 structure (Fig. 2). Our research group has developed compounds 1 and 2, which demonstrated remarkable inhibitory activity and selectivity for PARP7. Additionally, they possessed favorable PK properties (F > 90 %) and demonstrated significant anti-tumor effects (TGI > 67 %) in CT26 syngeneic mouse models [18], [22]. At the same time, compound 2 (KMR-206) was reported as a novel selective inhibitor of PARP7, while no in vivo studies were displayed [23]. Recently, He et al. [24] reported a PARP7 inhibitor with two chiral centers (Compound 3) that exhibit good inhibitory activity against PARP7 (IC50: 0.56 nM). In addition, many other pharmaceutical industry and academic institutions have also reported some PARP7 inhibitors. However, the exact structure of the preferred compound has not yet been confirmed [25], [26], [27].

The objective of this research is to discover a novel compound that displays strong inhibition towards PARP7. To achieve this, we utilized RBN-2397 as the lead compound and employed rational drug design to get a series of novel compounds. Notably, compound XYL-1 demonstrated the highest potency in inhibiting PARP7 enzymatic activity, with an IC50 value of 0.6 nM. In addition, the inhibitory activity of XYL-1 on PARP1 (IC50 > 1.0 μM) was weaker than that of RBN-2397 (IC50 = 29.0 nM). Mechanism studies showed that XYL-1 could enhance the type Ⅰ interferon signaling in vitro. What’s more, XYL-1 could significantly inhibit tumor growth in the CT26 syngeneic mouse model. In summary, XYL-1 is a highly potent PARP7 inhibitor and shows prospects as a potential candidate compound for subsequent preclinical evaluation.