Preclinical Profile of RP14042, a novel, selective, and potent small molecule inhibitor of PARP7

Background: Poly (ADP-ribose) polymerase (PARP)-7 is a member of PARP family and is classified as monoPARP as it catalyzes the transfer of single units of ADP-ribose (MARylation) onto its substrates to exert its physiological functions. It is involved in several cellular processes, including responses to hypoxia, innate immunity, and regulation of nuclear receptors. In addition, PARP7 is overexpressed/amplified in variety of cancers including Ovarian, Breast, Pancreatic ductal adenocarcinoma (PDAC), Non-small cell lung carcinoma (NSCLC) and Squamous cancers. PARP-7 acts as a negative regulator of nucleic acid sensing in tumor cells leading to suppression of Type I interferon (IFN) response. Preclinical studies have demonstrated that inhibition of PARP-7 restores Type I interferon (IFN) signaling leading to tumor cell growth inhibition and activation of the immune system, thereby contributing to tumor regression. Herein, we describe the preclinical profile of RP14042, a novel, selective, and potent small molecule inhibitor of PARP7. Material & Methods: Enzymatic potency was evaluated using a PARP Chemiluminescent Activity Assay Kit (BPS biosciences). Cell growth was determined following incubation with RP14042 as a single agent in various solid tumor cell lines. Cell cycle was evaluated following incubation of cells with compound for 72 h, subsequent staining with Propidium Iodide, and analysis by flow cytometry. Expression of p-STAT1 and p-IRF3 were determined in NCI-H1373 cell line by Western blotting. Pharmacokinetic properties of the molecule were also evaluated. Results: RP14042 inhibited PARP7 with an IC50 of 10.2 nM with selectivity over other members of the PARP family. Compound caused a dose-dependent growth inhibition of NCI-H1373, a PARP-7 overexpressing, cell line with an GI50 of 0.5 μM without any effect on the growth in low PARP-7 expressing cell lines. Incubation of NCI-H1373 cells with RP14042 caused G0/G1 cell cycle arrest. Inhibition of PARP7 by RP14042 in NCI-H1373 induced STAT1 and IRF3 phosphorylation suggesting restoration of Type I IFN signaling. Pharmacokinetic studies in rodents indicated high oral bioavailability with favorable plasma concentrations relevant for efficacy. Conclusion: Data demonstrate the therapeutic potential of RP14042 in PARP7 overexpressing tumors No conflict of interest.