Abstract
Abstract Although PARP inhibitors (PARPi) are very successful on the treatment of BRCA-mutant cancer, the tumor spectrum targeted by PARPi is quite narrow. Interestingly, Poly(ADP-ribose) Glycohydrolase (aka PARG), the major dePARylation enzyme, has emerged as a promising therapeutic target for cancer treatment. Here, we have developed a cell membrane permeable PARG inhibitor with subnanomolar IC50. SYX3759 directly binds to the catalytic domain of PARG and induces significant accumulation of PARylation at DNA lesions, where it traps numerous DNA repair factors, such as XRCC1. Compared to PARPi, such as Olaparib, SYX3759 shows selective and potent cytotoxicity on a broader spectrum of homologous recombination deficient (HRD) tumors both in vitro and in vivo. Moreover, SYX3759 is well tolerated at the highest dose tested without obvious adverse effect on hematopoiesis. Collectively, SYX3759 is a potent PARG inhibitor both in vitro and in vivo warranting future clinical trials for the treatment of HRD cancers and beyond. Citation Format: Xuzhen Tang, Yaqi Cui, Lanqiao Zhang, Huihui Jin, Zeqiong Xu, Hu He, Chongxun Ge, Song Liu, Xiaochun Yu, Song Shi. Pre-clinical study of SYX3759, a novel PARG inhibitor for the treatment of homologous recombination deficient malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6184.
Published Version
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