delivery molecules to selectively release anticancer drugs through the inhibition of
LSD1 (Fig. 6a). PCPA-drug conjugates (PDCs) are expected to be recognized by
LSD1 and to inactivate it in a similar manner to PCPA itself, i.e., via a singleelectron transfer mechanism (Fig. 6b). Subsequently, the drug should be released
together with the linker moiety of the PDCs through hydrolysis of the imine
intermediate, and an ensuing intramolecular cyclization should eventually separate
the linker from the drug. Thus, PDCs could serve as delivery molecules that
selectively release an anticancer drug upon binding to LSD1. This method would
significantly reduce adverse effects as such molecules are inactive toward normal
cells where the expression of LSD1 is low. As a PDC prototype, we have designed
and synthesized PCPA-tamoxifen conjugates (Fig. 2) targeting breast cancer cells
(Fig. 6b), which release 4-hydroxytamoxifen in the presence of LSD1 in in vitro
assays. Furthermore, PCPA-tamoxifen conjugates inhibit the growth of breast cancer
cells through the simultaneous inhibition of LSD1 and ERα without exhibiting
cytotoxicity toward normal cells. These results demonstrated that PDCs are a useful
anticancer drug delivery tool that may facilitate the selective release of drugs in
cancer cells.
Previously, Schüle and co-workers tested whether pargyline (Fig. 2), a well-known
MAO inhibitor, inhibits LSD1 and found that it blocks the demethylation of H3K9 by
LSD1 and consequently blocks AR-dependent transcription [7]. Based on this report,
Jung and co-workers discovered new small-molecule inhibitors of LSD1 containing a
propargylamine warhead [70]. Druglike LSD1 inhibitors with a propargylamine moiety, such as T5342129 (Fig. 2), showed histone hypermethylation in breast cancer cells.
Phenelzine (Fig. 2), a MAO inhibitor, has also been reported to inhibit LSD1,
although its inhibitory activity and selectivity for LSD1 are very low [51, 52, 71,
72]. Cole and co-workers identified analogs of phenelzine and their LSD1 inhibitory
properties [73]. A novel phenelzine analog (bizine) (Fig. 2) containing a phenylbutyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was
selective versus MAO-A, MAO-B, and LSD2. Bizine was found to be effective in
modulating bulk histone methylation in cancer cells, and ChIP-seq experiments
revealed a statistically significant overlap in the H3K4 methylation pattern of
genes affected by bizine and those altered in LSD1
À/À cells. Treatment of two
cancer cell lines, LNCaP and H460, with bizine resulted in a reduction of proliferation rate, and bizine showed additive to synergistic effects on cell growth when
used in combination with two of the five HDAC inhibitors tested. Moreover, neurons
exposed to oxidative stress were protected by the presence of bizine, suggesting
potential applications in neurodegenerative diseases.
Not only irreversible LSD1 inhibitors, which are derived from MAO inhibitors,
but also reversible LSD1 inhibitors have been identified.
Woster and co-workers reported that (bis)guanidines, (bis)biguanides, and their
urea and thiourea isosteres, such as 4 and 5 (Fig. 2), are potent inhibitors of LSD1
and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor
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T. Suzuki
LSD1 (Fig. 6a). PCPA-drug conjugates (PDCs) are expected to be recognized by
LSD1 and to inactivate it in a similar manner to PCPA itself, i.e., via a singleelectron transfer mechanism (Fig. 6b). Subsequently, the drug should be released
together with the linker moiety of the PDCs through hydrolysis of the imine
intermediate, and an ensuing intramolecular cyclization should eventually separate
the linker from the drug. Thus, PDCs could serve as delivery molecules that
selectively release an anticancer drug upon binding to LSD1. This method would
significantly reduce adverse effects as such molecules are inactive toward normal
cells where the expression of LSD1 is low. As a PDC prototype, we have designed
and synthesized PCPA-tamoxifen conjugates (Fig. 2) targeting breast cancer cells
(Fig. 6b), which release 4-hydroxytamoxifen in the presence of LSD1 in in vitro
assays. Furthermore, PCPA-tamoxifen conjugates inhibit the growth of breast cancer
cells through the simultaneous inhibition of LSD1 and ERα without exhibiting
cytotoxicity toward normal cells. These results demonstrated that PDCs are a useful
anticancer drug delivery tool that may facilitate the selective release of drugs in
cancer cells.
Previously, Schüle and co-workers tested whether pargyline (Fig. 2), a well-known
MAO inhibitor, inhibits LSD1 and found that it blocks the demethylation of H3K9 by
LSD1 and consequently blocks AR-dependent transcription [7]. Based on this report,
Jung and co-workers discovered new small-molecule inhibitors of LSD1 containing a
propargylamine warhead [70]. Druglike LSD1 inhibitors with a propargylamine moiety, such as T5342129 (Fig. 2), showed histone hypermethylation in breast cancer cells.
Phenelzine (Fig. 2), a MAO inhibitor, has also been reported to inhibit LSD1,
although its inhibitory activity and selectivity for LSD1 are very low [51, 52, 71,
72]. Cole and co-workers identified analogs of phenelzine and their LSD1 inhibitory
properties [73]. A novel phenelzine analog (bizine) (Fig. 2) containing a phenylbutyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was
selective versus MAO-A, MAO-B, and LSD2. Bizine was found to be effective in
modulating bulk histone methylation in cancer cells, and ChIP-seq experiments
revealed a statistically significant overlap in the H3K4 methylation pattern of
genes affected by bizine and those altered in LSD1
À/À cells. Treatment of two
cancer cell lines, LNCaP and H460, with bizine resulted in a reduction of proliferation rate, and bizine showed additive to synergistic effects on cell growth when
used in combination with two of the five HDAC inhibitors tested. Moreover, neurons
exposed to oxidative stress were protected by the presence of bizine, suggesting
potential applications in neurodegenerative diseases.
Not only irreversible LSD1 inhibitors, which are derived from MAO inhibitors,
but also reversible LSD1 inhibitors have been identified.
Woster and co-workers reported that (bis)guanidines, (bis)biguanides, and their
urea and thiourea isosteres, such as 4 and 5 (Fig. 2), are potent inhibitors of LSD1
and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor
212
T. Suzuki