Abstract 4232: DW91170B: A novel potent EZH1/2 dual inhibitor for adrenocortical carcinoma treatment

Abstract Adrenocortical carcinoma (ACC) is an aggressive cancer that occurs in the adrenal cortex with a poor prognosis, and its 5-year survival rate is less than 60%. Previous studies have characterized molecular and cellular alterations in ACC, including changes in p53, the WNT-β-catenin pathway, PKA, and chromatin remodeling pathways. EZH2 (Enhancer of zeste homolog 2), a catalytic subunit of PRC2 (polycomb repressive complex 2), also exhibits abnormal characteristics in ACC. EZH2 has been reported to be overexpressed in ACC patients and is associated with disease progression and survival rates. Here, we present DW91170B, a novel and potent dual inhibitor of EZH1/2, as a candidate for the treatment of adrenocortical carcinoma. DW91170B induces histone modification by reducing the trimethylation of H3K27, suppresses cell viability, and induces apoptosis in adrenal cancer cells. Additionally, DW91170B affects the molecular and cellular characteristics of adrenal cancer cells. Specifically, treatment with DW91170B reduces the expression of HSD3B2 and CYP11B1, genes involved in steroidogenic process. As a result, aldosterone and cortisol secretion induced by forskolin is inhibited by DW91170B. Long-term treatment with DW91170B decreases the expression of transcription regulators such as β-catenin and SF-1. These changes in transcriptional complex were confirmed through RNA sequencing, revealing alterations in gene expression. Among the differentially expressed genes, those related to epithelial-mesenchymal transition (EMT) and apical junctions were notably affected. Functional changes were further confirmed by EMT marker protein expression and a wound healing assay. The in vivo efficacy of DW91170B was assessed in two adrenal cancer models. NCI-H295R cells, which have high expression EZH2, and SW13 cells, which carry a SMARCA4 mutation that is susceptible to synthetic lethality from EZH2 inhibition, were used. DW91170B effectively inhibited tumor growth in both models. In summary, the novel EZH1/2 inhibitor DW91170B exhibits anti-tumor efficacy in adrenocortical carcinoma. These effects appear to be mediated by alterations in cancer cell characteristics and the inhibition of cell survival. Citation Format: Doc-Gyun Jeong, Yeonkyung Oh, Woon Heo, DongHyuk Shin, Jung Hee Kim, Emilia Moonkyung Youm, Jihyun Youm, Kiyoon Kim, Sangho Lee, Yun-Ha Hwang. DW91170B: A novel potent EZH1/2 dual inhibitor for adrenocortical carcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4232.