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
  • 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. [email protected] [email protected].
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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