LAUSR

Introduction: Global changes in the epigenetic landscape are known as the hallmark in cancer and the histone demethylase Lysine-specific demethylase 1 (LSD1) is one of the novel target for the therapy of various malignant diseases and LSD1 overexpression is associated with poor prognosis in various cancers. LSD1-mediated epigenetic modification is known to play a key role in the regulation of gene expression by removing the methyl groups from methylated lysine 4 and lysine 9 of histone H3. Alterations in histone methylation lead to aberrant silencing of expression of multiple genes involved in tumor survival and in cell cycle. Moreover, 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). Herein, Hanmi introduces, a safe drug profile of the novel LSD1 inhibitor, H97211on hematopoiesis differentiation by reversible binding on LSD1. Materials and Methods: Novel reversible LSD1 inhibitor, HM97211 was designed and synthesized as the active biologic inhibitory compound against the SCLC cells. The binding mode on reversibility for HM97211 and biochemical activity on LSD1 were determined by LSD1 Fluorescent assay kit (BPS Bioscience; Venkataswamy Sorna et al, 2013). In vitro proliferation assay was performed by using the CellTiter-Glo (Promega) In vivo therapeutic efficacy of HM97211 was evaluated in NCI-H1417 xenograft mice models. 5 x 106 NCI-H1417 cells/mouse were implanted subcutaneously and mice were treated by daily oral administration of (30mg/kg) HM97211. Tumor sizes were measured and tumor samples were analyzed of the mechanisms of action. Results: HM97211 enhanced not only global methylation of H3K4 but also apoptotic signaling in NCI-H1417 cell line. HM97211 altered expression of neuroendocrine factor ASCL1, inducing programmed cell death in SCLC cells. In NCI-H1417 xenograft models, daily oral administration of HM97211 induced tumor regression without remarkable toxicity. Analyses of tumor samples revealed the important role of potent small molecule LSD1 inhibitor in neuroendocrine-associated transcription and cell proliferation of SCLC. Conclusion: Collectively, results of this study suggested that novel reversible LSD1 inhibitor, HM97211, can be a strong therapeutic agent for SCLC patients. Hanmi presents a new insight to epigenetics application in anticancer therapy. Citation Format: InHwan Bae, JiSook Kim, ChangHee Park, Hyeongki Kim, Namgoong Gwangmog, Joo-Yun Byun, Seokhyun Hong, Teahun Song, JaeHo Lee, Kyuhang Lee, Myoungsil Ko, Cheolkyung Kim, YoungMi Lee, Ho Jeong Lee, YoungHoon Kim, YoungGil Ahn, KweeHyun Suh, Sun-Jin Kim. Antitumor activity of novel reversible LSD1 inhibitor, HM97211 in preclinical models of SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4871.