Abstract 6275: DW91170: A novel potent EZH1/2 dual inhibitor for lymphoma treatment

Abstract EZH2(Enhancer of zeste homolog2) is a catalytic subunit of PRC2 (polycomb repressive complex 2) for chromatin remodeling through methyl transfer activity. Previous studies have reported correlation between EZH2 and cancer progression with overexpression and mutations in various cancers. EZH1, homolog of EZH2, also has been known to role in development and progression of cancers by complementarily replacing EZH2. In recent researches, EZH1/2 dual inhibition showed global epigenetic modification on histone methylation and acetylation. Also, cancers associated with change in epigenetic factors such as mutations in subunit of SWI/SNF responded on EZH1/2 dual inhibition. Therefore, EZH1/2 dual inhibition is expected to be an effective strategy for cancer treatment. Herein, we present a novel potent EZH1/2 dual inhibitor, DW91170, as a promising candidate for treatment of lymphoma with improved anti-cancer activity. DW91170 selectively inhibited EZH1 and EZH2 enzyme activity. DW91170 brought about histone modification by reducing tri-methylation and enhancing acetylation of H3K27, which increased expression of target genes and cell cycle arrest was confirmed by treatment of DW91170. DW91170 showed effective tumor growth inhibition in two types of EZH2 hot spot mutation models. In Pfeiffer (A677 mutation) and WSU-DLCL2 (Y641 mutation) CDX models, DW91170 showed improved tumor regression activity with no significant abnormal signs such as weight loss. In order to verify the potential of DW91170 in R/R-lymphoma patients, the anti-cancer effect was evaluated in Rituximab-resistant cell line and R/R-DLBCL patient-derived PDX model. As a result, DW91170 efficiently inhibited Rituximab-resistant cell proliferation and suppressed tumor growth in R/R-DLBCL PDX model more significantly compared to other EZH inhibitors. Moreover, DW91170 has a good absorption profile that works in a physiological condition. Taken together, we demonstrated that DW91170, a dual epigenetic regulator of EZH1 and EZH2, showed great anti-tumor activities in various lymphoma cell lines and animal models such as CDX and PDX. We are currently trying to expand indication into solid tumor to find a targetable population in clinical trials. Citation Format: Doc-Gyun Jeong, Woon Heo, DongHyuk Shin, Yeonkyung Oh, Sangho Lee, Seongsu Jeong, Whuijung Park, Jiyoung Woo, Chanseok Jeon, Subin Kim, Jaekyung Lim, Yun-Ha Hwang. DW91170: A novel potent EZH1/2 dual inhibitor for lymphoma treatment. [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 6275.