title: A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells.
abstract: Dysregulation of lysine (K)-specific demethylase 1A (LSD1), also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here, we describe the antileukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroid leukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells. Mechanistically, T-3775440 disrupted the interaction between LSD1 and growth factor-independent 1B (GFI1B), a transcription factor critical for the differentiation processes of erythroid and megakaryocytic lineage cells. Knockdown of LSD1 and GFI1B recapitulated T-3775440-induced transdifferentiation and cell growth suppression, highlighting the significance of LSD1-GFI1B axis inhibition with regard to the anti-AML effects of T-3775440. Moreover, T-3775440 exhibited significant antitumor efficacy in AEL and AMKL xenograft models. Our findings provide a rationale for evaluating LSD1 inhibitors as potential treatments and indicate a novel mechanism of action against AML, particularly AEL and AMKL. Mol Cancer Ther; 16(2); 273-84. ©2016 AACR.
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Gamo
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yabuki
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takagi
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Toyoshima
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Morimoto
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyashita
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Dairiki
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hikichi
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tomita
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomita
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
authors.affiliation: Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Iwatani
authors.affiliation: Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Ryujiro
authors.initials: R
authors.lastname: Hara
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nomura
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. kazuhide.nakamura@takeda.com ken.tsuchida@takeda.com.
authors.forename: Ken
authors.initials: K
authors.lastname: Tsuchida
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. kazuhide.nakamura@takeda.com ken.tsuchida@takeda.com.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis / Q000235:genetics; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C111977:GFI1B protein, human; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D056466:Histone Demethylases; C495195:KDM1A protein, human