P015, a highly selective PARP7&12 dual inhibitor

Background: The poly(ADP-ribose) polymerase (PARP) family plays critical roles in DNA damage repair, cellular stress responses, and tumor immune modulation. Among them, PARP7 and PARP12 have been implicated in innate immunity and tumor microenvironment remodeling. Selective inhibition of PARP7&12 holds promise for cancer therapy by modulating immune responses and cell survival pathways. However, potent and selective small-molecule inhibitors targeting PARP7&12 remain scarce, creating an urgent need for the development of candidate compounds with superior enzymatic inhibitory activity. Methods and Materials: Based on structure-activity relationship (SAR) studies and accelerated by the Convalife "AIDRUG.WORK" molecular design platform, we designed and optimized small-molecule inhibitors targeting PARP7&12, leading to the identification of the candidate compound P015. In vitro enzymatic assays were performed to evaluate the inhibitory activity of P015 against human PARP7 and PARP12. IC 50 values were calculated by fitting concentration-response curves. The current work primarily focuses on characterizing enzymatic-level activity to validate the feasibility of P015 as a PARP7&12 inhibitor. Results: Enzymatic assay results demonstrated that P015 exhibited potent inhibitory activity against both PARP7 and PARP12, with IC 50 values below 10 nM for both enzymes. These findings indicate that P015 possesses exceptionally strong affinity and inhibitory potency for PARP7&12 at the enzymatic level, establishing a foundation for further investigation of P015 as a highly active PARP7&12 inhibitor. Conclusions: We have identified and preliminarily characterized P015, a small-molecule inhibitor with sub-10 nM IC 50 values against PARP7&12 at the enzymatic level. Although current experimental data are primarily derived from in vitro enzyme activity assays, the results suggest that P015 has significant potential for further cellular and in vivo pharmacological and mechanistic studies, and may be developed as a novel anti-cancer candidate drug targeting the PARP7&12 pathway.