Abstract 1135: Antitumor activity of novel reversible LSD1 inhibitors in preclinical models of AML and SCLC

Abstract Lysine-specific demethylase 1 (LSD1) has become a biologically important and validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and such epigenetic dysregulation plays a critical role in pathogenesis of various types of cancers such as acute myeloid leukemia (AML) or small cell lung cancer (SCLC). In this study, we introduce HM97346 and its derivatives as novel LSD1 inhibitors, and report a therapeutic potential for AML and SCLC patients based on several preclinical characterization and assessment. HM97346 and its derivatives were designed and synthesized as novel reversible inhibitors of LSD1. Standard cell proliferation assay, immunoblotting, biomarker expression, and apoptosis analysis were carried out to validate their potency in vitro studies using different AML and SCLC cell lines. The in vivo antitumor activity was evaluated in AML and SCLC cell xenograft mouse models. Tumor sizes were measured and tumor samples were analyzed to define the mechanisms of action. HM97346 and its derivatives showed strong inhibition on LSD1 enzymatic activity in biochemical assay and promoted the methylations of histone H3 lysine 4 (H3K4) in both SCLC and AML cells. They reduced the expression of neuroendocrine factors ASCL1 in SCLC cells, effectively and dose-dependently. Moreover, in human AML cell lines, they stimulated cellular differentiation by disrupting LSD1-GFI1 complex and induced transcription factor PU.1 as well as myeloid differentiation markers CD86 and CD11b. As a result, they significantly inhibited cellular proliferation and induced apoptosis in studies using AML and SCLC cells. Oral administration of HM97346 and its derivatives inhibited tumor growth in human AML and SCLC cell xenograft mouse models studies. These antitumor effects dramatically increased in combination with standard chemotherapies. In conclusion, HM97346 and its derivatives, new synthesized reversible LSD1 inhibitors, showed potential anticancer activity in preclinical AML and SCLC models. Moreover, these compounds could provide a new insight and possibility in cancer therapy through epigenetic modulation as not only monotherapy but also combination therapy. Citation Format: Joo-Yun Byun, Won Jong Lee, Won jung Kim, Minjeong Kim, Inhwan Bae, Seokhyun Hong, Yu-Yon Kim, Hyunjin Park, Eunyoung Kim, Young Hoon Kim, Young Gil Ahn, Kwee Hyun Suh. Antitumor activity of novel reversible LSD1 inhibitors in preclinical models of AML and SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1135.