2. Academic Validation
  3. A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells

A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells

  • Mol Cancer Ther. 2017 Feb;16(2):273-284. doi: 10.1158/1535-7163.MCT-16-0471.
Yoshinori Ishikawa 1,  Kanae Gamo 1,  Masato Yabuki 1,  Shinji Takagi 1,  Kosei Toyoshima 1,  Kazuhide Nakayama 1,  Akiko Nakayama 1,  Megumi Morimoto 1,  Hitoshi Miyashita 1,  Ryo Dairiki 1,  Yukiko Hikichi 1,  Naoki Tomita 1,  Daisuke Tomita 1,  Shinichi Imamura 1,  Misa Iwatani 2,  Yusuke Kamada 2,  Satoru Matsumoto 3,  Ryujiro Hara 1,  Toshiyuki Nomura 1,  Ken Tsuchida 4,  Kazuhide Nakamura 4
Affiliations

Affiliations

  • 1 Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
  • 2 Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
  • 3 Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
  • 4 Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. kazuhide.nakamura@takeda.com ken.tsuchida@takeda.com.
PMID: 27903753 DOI: 10.1158/1535-7163.MCT-16-0471
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.

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