title: Identification of JL1037 as a novel, specific, reversible lysine-specific demethylase 1 inhibitor that induce apoptosis and autophagy of AML cells.
abstract: Lysine-specific demethylase 1 (LSD1) has been recognized as a potential therapeutic target for acute myeloid leukemia (AML). Herein, we identified a novel LSD1 inhibitor, JL1037, via Computer Aided Drug Design technology. JL1037 is a potent, selective and reversible LSD1 inhibitor with IC50s of 0.1 μM and >1.5 μM for LSD1 and monoamine oxidases A/B (MAO-A/B), respectively. Treatment of THP-1 and Kasumi-1 cell lines with JL1037 resulted in dose dependent accumulation of H3K4me1 and H3K4me2, the major substrates of LSD1, as well as inhibition of cell proliferation, blockade of cell cycle and induction of apoptosis. Further investigations demonstrated that JL1037 could upregulate cell cycle-related proteins P21, P57, pro-apoptotic protein Bax and downregulate anti-apoptosis proteins Bcl-2 and Bcl-XL. JL1037 appeared to activate autophage response in AML cell lines as well as primary cells from AML patients by increasing LC3-II expression and the formation of autophagosomes and autolysosomes in cytoplasm. Co-treatment with autophagy inhibitor chloroquine (CQ) enhanced JL1037-induced cell apoptosis. Moreover, daily intravenous administration of JL1037 tended to reduce tumor burden and prolong the survival of t(8;21) leukemia mice. In conclusion, JL1037 exhibited potent anti-leukemia effect and could be a potential therapeutic agent for AML treatment.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Shouyun
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Saisai
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Fujian Jinler Pharmaceuticals, Jiangle County, Fujian 353300, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Fujian Jinler Pharmaceuticals, Jiangle County, Fujian 353300, China.
authors.forename: Shuzu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Fujian Jinler Pharmaceuticals, Jiangle County, Fujian 353300, China.
authors.forename: Joe Zhongxiang
authors.initials: JZ
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Yingxi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Rao
authors.affiliation: Fujian Jinler Pharmaceuticals, Jiangle County, Fujian 353300, China.
authors.forename: Chengjun
authors.initials: C
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D051379:Mice; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: LSD1 inhibitor; apoptosis; autophagy; leukemia; proliferation inhibition