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.

Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1

“…4 Aside from this role, it has become clear that LSD1 plays important scaffolding roles as part of the CoREST complex, 5 especially in controlling the interaction with transcription factors such as growth factor independence (GFI) 1 and 1b. [6][7] LSD1 and GFI1 in combination appear to balance the regulation of hematopoietic cell proliferation and differentiation in hematopoietic stem and progenitor cells. 8…”

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

“…Some LSD inhibitors, ORY-1001, Tranylcypromine, and GSK9552, have reached clinical trials but are pending results for different cancers. Pre-clinical results show exciting results for LSD inhibitors in AML, providing a good possibility of translating into clinic [179,180]. …”

Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases

“…Recently, Takeda Pharmaceuticals reported another N -alkylated 2-PCPA derivative as an LSD1 inhibitor 20 . T-3775440 ( 8 , Fig.…”

“…T-3775440 ( 8 , Fig. 2) inhibits LSD1 irreversibly in vitro with an IC 50 of 2.1 or 20 nM in the presence or absence of CoREST, respectively (Table 2), and exhibits rapid antiproliferative and pro-apoptotic activities against acute erythroid leukemia (AEL) and acute megakaryoblastic leukemia (AMKL) cells 20 …”