Abstract 3089: XNW5004: a novel EZH2 inhibitor efficacious in multiple cancer xenograft models as a single agent and in combination studies
Authors: Hu Yonghan , Peng Wei , Zhang Zhe , Wu Zhenwei , Chen Xi , Huang Yan , Li Xin , Liu Cungang , Liu Xiaojun , Shi Qifeng , Wang Xufang , Wang Wengui , Wei Haiyang , Wu Yuchuan , Xian Jun , Xu Linfeng , Zhang Lina , Zhao Jinfeng , Le Meijie , Qiang Jing 
Published: June 2023

Enhancer of zeste homolog 2 (EZH2) is the histone methyltransferase component of polycomb repressive complex 2 (PRC2) that can regulate gene expression by H3K27 trimethylation (H3K27Me3). EZH2 also mediates PRC2-dependent non-histone protein methylation or directly methylates non-histone proteins to regulate gene expression independent of PRC2. EZH2 plays an important role in regulation of cell cycle, autophagy, apoptosis and cell senescence. Mutated or overexpressed EZH2 associates with cancer initiation, progression, drug resistance and immunity regulation in cancer. XNW5004 is a rationally designed selective EZH2 inhibitor which potently inhibits both wild type and mutant EZH2. XNW5004 significantly suppresses level of H3K27Me3, arrests cell cycle in G1/S phase and promotes apoptosis in tumor. XNW5004 exhibits strong antitumor activity in EZH2-mutant lymphoma xenograft models, such as Karpas422 (Y641N), Pfeiffer (A677G) and SU-DHL-10 (Y641F). Since inhibition of EZH2 synthetically lethal in SWI/SNF subunits mutated cancers, XNW5004 exhibits dose-dependent efficacy in solid tumor models such as G401 (SMARCB1 deficient) and COV434 (SMARCA2/SMARCA4 deficient) cancer cell lines and xenografts. In prostate cancer cells, EZH2 can bind to the promoter of androgen receptor (AR) gene and activate AR expression. In PARPi-treated cancer cells, inhibition of PARP (poly-ADP-ribose polymerase) diminishes PARylation of EZH2 to result in reactivation of EZH2 and drug resistance to PARPi. In tumor microenvironment, inhibition of EZH2 promotes differentiation of T cells and NK cells, enhances antigen presentation ability of dendritic cells, and increases cytokine/chemokine secretion to recruit T cells into tumor tissue. Based on the above mechanisms, XNW5004 could potentially improve efficacy of ARi, PARPi and anti-PD-1. We have verified the synergistic effects of those combinations in multiple solid tumor xenograft models. In pharmacokinetic studies, XNW5004 has excellent oral bioavailability and exposure. XNW5004 shows good toxicological profile as well, has a wide therapeutic window in rats and dogs, and the risk of clinical safety was controllable. In summary, XNW5004 is a potent EZH2 inhibitor with promising efficacy, pharmacokinetic and safety properties. XNW5004 is expected to be a potent therapeutic candidate in cancer treatment and is now in Phase II clinical trial for both liquid and solid tumors.

Citation Format: Yonghan Hu, Wei Peng, Zhe Zhang, Zhenwei Wu, Xi Chen, Yan Huang, Xin Li, Cungang Liu, Xiaojun Liu, Qifeng Shi, Xufang Wang, Wengui Wang, Haiyang Wei, Yuchuan Wu, Jun Xian, Linfeng Xu, Lina Zhang, Jinfeng Zhao, Meijie Le, Jing Qiang. XNW5004: a novel EZH2 inhibitor efficacious in multiple cancer xenograft models as a single agent and in combination studies [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 3089.