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Abstract PARP7 is a mono-ADP-ribosyl transferase that catalyzes the transfer of single units of ADP-ribose onto substrate proteins to regulate their functions. One of its substrates is TANK binding kinases 1 (TBK1), whose MARylation by PARP7 inhibits its activation and thereby represses the type I IFN response to cytosolic nucleic acid. PARP7 is upregulated in many kinds of cancers and acts as a brake in cytosolic nucleic acid sensing, which leads to the suppression of type I IFN signaling and immune response. Therefore, PARP7 is a novel and promising target in cancer immunotherapy. Herein, we describe the discovery of a novel small molecule NSP-5033 as a dual PARP7/PARP12 inhibitor, which potently inhibits PARP7 and PARP12 enzymes with sub-nanomolar and low nanomolar activities, respectively. It displayed potent anti-proliferative activities against a number of cancer cell lines in vitro. NSP-5033 also increased the mRNA level of IFNβ and CXCL10 and stimulated STAT1 phosphorylation, suggesting that it restored the type I IFN response in tumor cells. With excellent ADME and pharmacokinetic properties, NSP-5033 demonstrated potent in vivo efficacy in human lung cancer xenografts with tumor regression and induced antitumor immunity in tumor-bearing immunocompetent mice. NSP-5033 has been nominated as a preclinival candidate for treatment of solid tumors and is undergoing IND-enabling studies. Citation Format: Qin Chen, Qionglin Huang, Ke Zhang, Yuli Hao, Zixuan Wang, Bing Li. Discovery of NSP-5033: A novel and potent PARP7/12 dual inhibitor abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7588.
Chen et al. (Fri,) studied this question.