cells in vitro [31]. They also reported a series of small-molecule amidoximes, such as
6 (Fig. 2), which are moderate inhibitors of recombinant LSD1 but produce dramatic
changes in methylation at the H3K4 chromatin mark in Calu-6 lung carcinoma cells
[74]. In addition, these analogs increased cellular levels of LSD1 target genes, such
as secreted frizzle-related protein 2, H-cadherin, and the transcription factor
GATA4.
Wu et al. reported 3-(piperidin-4-ylmethoxy)pyridine-containing compounds,
such as 7 (K i ¼ 29 nM) (Fig. 2), as potent LSD1 inhibitors [75]. These compounds
exhibit high selectivity (>160Â) against related MAO-A and MAO-B. Enzyme
kinetics and docking studies suggested that they are competitive inhibitors against
a dimethylated H3K4 substrate and proposed a possible binding mode. The potent
LSD1 inhibitors can increase cellular H3K4 methylation and strongly inhibit the
proliferation of several leukemia and solid tumor cells with EC 50 values as low as
280 nM, while they have negligible effects on normal cells.
A structure-based virtual screening of a compound library containing approximately two million small molecular entities has led to the identification of SP2509
(Fig. 2) as a reversible and selective LSD1 inhibitor (K i ¼ 31 nM) [76], although the
core N
0 -(2-hydroxybenzylidene)hydrazide motif was previously identified as a
pan-assay interference compound [77]. SP2509 inhibits the proliferation and survival of several cancer cell lines, including breast and colorectal cancer. It was also
reported that treatment with SP2509 attenuates the binding of LSD1 with the
corepressor CoREST, increases the permissive H3K4Me3 mark on the target gene
promoters, and increases the levels of p21, p27, and CCAAT/enhancer binding
protein α in cultured AML cells [78]. In addition, SP2509 inhibits colony growth
of AML cells. SP2509 also induces morphological features of differentiation in
cultured and primary AML blasts. Treatment with SP2509 alone significantly
improves the survival of immune-depleted mice following tail-vein infusion and
engraftment of cultured or primary human AML cells. Co-treatment of panobinostat,
a pan-HDAC inhibitor, and SP2509 synergistically improves survival in mice
engrafted with the human AML cells without exhibiting any toxicity.
Recently, Mould et al. identified reversible LSD1 inhibitors from a highthroughput screen and subsequent in silico modelling approaches [79]. Based on a
hit compound, they carried out scaffold hopping from GSK-690 (Fig. 2) [80, 81], an
analog of compound 7, to find compound 8 (Fig. 2), which has a K d value of 32 nM
and an EC 50 value of 0.67 μM, in a surrogate cellular biomarker assay. Compound
8 does not display the same level of hERG liability as that observed with GSK-690
and represents a promising lead for the further development of LSD1 inhibitors.
In addition, Sartori, Vianello, and co-workers discovered thieno[3,2-b]pyrrole-5carboxamide analog 9 (Fig. 2) as a potent reversible inhibitor of LSD1 [82, 83]. Compound 9 upregulated the expression of LSD1 target genes such as CD14, CD11b,
and CD86 in THP-1 cells, and it showed a remarkable anticlonogenic cell growth
effect on MLL-AF9 human leukemia cells.
It was also reported that polymyxins and the antibiotics polymyxins such as
polymyxin B and quinazolines such as E11 (Fig. 2) inhibit LSD1 by binding to
the entrance of the substrate cleft where their positively charged moiety interacts
Lysine-Specific Histone Demethylases 1/2 (LSD1/2) and Their Inhibitors
213
6 (Fig. 2), which are moderate inhibitors of recombinant LSD1 but produce dramatic
changes in methylation at the H3K4 chromatin mark in Calu-6 lung carcinoma cells
[74]. In addition, these analogs increased cellular levels of LSD1 target genes, such
as secreted frizzle-related protein 2, H-cadherin, and the transcription factor
GATA4.
Wu et al. reported 3-(piperidin-4-ylmethoxy)pyridine-containing compounds,
such as 7 (K i ¼ 29 nM) (Fig. 2), as potent LSD1 inhibitors [75]. These compounds
exhibit high selectivity (>160Â) against related MAO-A and MAO-B. Enzyme
kinetics and docking studies suggested that they are competitive inhibitors against
a dimethylated H3K4 substrate and proposed a possible binding mode. The potent
LSD1 inhibitors can increase cellular H3K4 methylation and strongly inhibit the
proliferation of several leukemia and solid tumor cells with EC 50 values as low as
280 nM, while they have negligible effects on normal cells.
A structure-based virtual screening of a compound library containing approximately two million small molecular entities has led to the identification of SP2509
(Fig. 2) as a reversible and selective LSD1 inhibitor (K i ¼ 31 nM) [76], although the
core N
0 -(2-hydroxybenzylidene)hydrazide motif was previously identified as a
pan-assay interference compound [77]. SP2509 inhibits the proliferation and survival of several cancer cell lines, including breast and colorectal cancer. It was also
reported that treatment with SP2509 attenuates the binding of LSD1 with the
corepressor CoREST, increases the permissive H3K4Me3 mark on the target gene
promoters, and increases the levels of p21, p27, and CCAAT/enhancer binding
protein α in cultured AML cells [78]. In addition, SP2509 inhibits colony growth
of AML cells. SP2509 also induces morphological features of differentiation in
cultured and primary AML blasts. Treatment with SP2509 alone significantly
improves the survival of immune-depleted mice following tail-vein infusion and
engraftment of cultured or primary human AML cells. Co-treatment of panobinostat,
a pan-HDAC inhibitor, and SP2509 synergistically improves survival in mice
engrafted with the human AML cells without exhibiting any toxicity.
Recently, Mould et al. identified reversible LSD1 inhibitors from a highthroughput screen and subsequent in silico modelling approaches [79]. Based on a
hit compound, they carried out scaffold hopping from GSK-690 (Fig. 2) [80, 81], an
analog of compound 7, to find compound 8 (Fig. 2), which has a K d value of 32 nM
and an EC 50 value of 0.67 μM, in a surrogate cellular biomarker assay. Compound
8 does not display the same level of hERG liability as that observed with GSK-690
and represents a promising lead for the further development of LSD1 inhibitors.
In addition, Sartori, Vianello, and co-workers discovered thieno[3,2-b]pyrrole-5carboxamide analog 9 (Fig. 2) as a potent reversible inhibitor of LSD1 [82, 83]. Compound 9 upregulated the expression of LSD1 target genes such as CD14, CD11b,
and CD86 in THP-1 cells, and it showed a remarkable anticlonogenic cell growth
effect on MLL-AF9 human leukemia cells.
It was also reported that polymyxins and the antibiotics polymyxins such as
polymyxin B and quinazolines such as E11 (Fig. 2) inhibit LSD1 by binding to
the entrance of the substrate cleft where their positively charged moiety interacts
Lysine-Specific Histone Demethylases 1/2 (LSD1/2) and Their Inhibitors
213