Abstract 4714: Preclinical evaluation of a novel LSD1 inhibitor SYHA1807 for the treatment of small cell lung cancer

Histone post translational modification is an important epigenetic regulation to activate or suppress specific gene expressions. Methylation which is dynamically regulated by methyltransferase and demethylase (e.g. lysine specific demethylase) is one of the mechanisms and is critical for cell cycle and differentiation. Lysine specific demethylase 1 (LSD1) is the first identified histone modifying enzyme that removes methyl from histone lysine and arginine residues. Its overexpression has been found in many human cancers, like blood, lung and breast cancers. Small cell lung cancer is a neuroendocrine cancer characterized as low differentiation, rapid metastatic spread and resistance to regular chemotherapy. Aberration of epigenetic regulation is a common feature in small cell lung cancer, like down regulation of tumor suppression gene and up regulation of oncogenes. LSD1 expression of small cell lung cancer patients is up regulated in tumor tissue but not in normal tissues. Dysregulated histone methylation may contribute to the tumor malignance and treatment resistance. Taken together, LSD1 activity inhibition may provide a promising treatment option for small cell lung cancer. A challenge in LSD1 drug development is how to maintain optimal therapeutic effects while reducing mechanism related hematological toxicity. Through scaffold hopping and thoroughly SAR exploration, a novel LSD1 inhibitor SYHA1807 has been identified. The exposure level of this candidate at lung tissue is about four times higher than in bone marrow. The ideal drug tissue distribution characteristics may provide further safety assurance in clinical application. Detailed ADME/PK, in vitro, in vivo properties and preliminary safety evaluation results will be presented. Note: This abstract was not presented at the meeting. Citation Format: Lingyun Wu, Hanyu Yang, Lele Zhao, Jianjun Sun, Jian Liu, Yuanfeng Xia, Chichung Chan, Shuhui Chen. Preclinical evaluation of a novel LSD1 inhibitor SYHA1807 for the treatment of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4714.