hematopoiesis is spared [62]. A single administration of NCD38 causes the in vivo
eradication of primary MDS-related leukemia cells with a complex karyotype. Mechanistic studies showed that NCD38 elevates H3K27ac level on enhancers of the LSD1
signature genes and derepresses the super-enhancers of hematopoietic regulators that
are silenced abnormally by LSD1.
In addition to the antiproliferative activity of NCD38 in differentiated cancer
cells, NCD38 is also able to inhibit cancer stem cell formation and the maintenance
of human metastatic breast cancer cells, thus reverting them to epithelial form
[63]. The pharmacological inhibition of LSD1 using NCD38 significantly reduces
cell viability and neurosphere formation and induces apoptosis of glioma stem cells
(GSCs) with little effect on differentiated cells [64]. In preclinical studies using
orthotopic models, NCD38 significantly reduces GSC-driven tumor progression and
improves mouse survival. Mechanistic studies showed that NCD38 causes apoptosis
of GSCs by inducing the activation of the unfolded protein response pathway.
Thus, NCD38 and its derivatives are considered candidates for anticancer agents
as well as tools for probing the biology of LSD1. Currently, IMG-7289, an NCD38
mimetic, is being evaluated in a phase 1/2 clinical trial for the treatment of AML
and MDS (http://www.imagobio.com/imago-biosciences-doses-first-patients-inphase-12-study-of-img-7289-in-myelofibrosis/).
GlaxoSmithKline and Oryzon Genomics discovered potent and selective LSD1
inhibitors GSK2879552 and ORY-1001, respectively (Fig. 2) [65, 66]. GSK2879552
and ORY-1001 exhibit antileukemia activity and are currently undergoing clinical
trials for AML treatment. In addition, screening for cancer cell lines revealed that
small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition by PCPA analogs,
including GSK2879552 [65]. GSK2879552 exhibits DNA hypomethylation in
SCLC lines, suggesting that DNA hypomethylation can be used as a predictive
biomarker of LSD1 inhibitory activity.
In addition, Oryzon Genomics developed LSD1/MAO-B inhibitor ORY-2001.
ORY-2001 prevents the development of memory deficit in SAMP8 mice through the
induction of neuronal plasticity and the reduction of neuroinflammation [49]. Currently, ORY-2001 is being evaluated in a phase 1 clinical trial for the treatment of
Alzheimer’s disease.
Vianello et al. reported a novel PCPA derivative 1 (Fig. 2) as a potent inhibitor of
LSD1 [67]. PCPA derivative 1 strongly inhibits the clonogenic potential of acute
leukemia cell lines. Furthermore, compound 1 exhibits in vivo efficacy after oral
administration, inducing a 62% increase in survival in a mouse leukemia model.
Mai and co-workers identified hybrid LSD1/JmjC-domain containing histone
lysine demethylase inhibitors by coupling the skeleton of PCPA, an LSD1 inhibitor,
with 4-carboxy-4-carbomethoxy-2,2-bipyridine or 5-carboxy-8-hydroxyquinoline,
two 2-oxoglutarate competitive templates developed for JmjC inhibition [68]. The
hybrid compounds were validated as potential antitumor agents in cells. Compounds
2 and 3 (Fig. 2) caused growth arrest and substantial apoptosis in LNCaP prostate
and HCT116 colon cancer cells with an increase in H3K4 and H3K9 methylation
levels in the cells.
210
T. Suzuki
eradication of primary MDS-related leukemia cells with a complex karyotype. Mechanistic studies showed that NCD38 elevates H3K27ac level on enhancers of the LSD1
signature genes and derepresses the super-enhancers of hematopoietic regulators that
are silenced abnormally by LSD1.
In addition to the antiproliferative activity of NCD38 in differentiated cancer
cells, NCD38 is also able to inhibit cancer stem cell formation and the maintenance
of human metastatic breast cancer cells, thus reverting them to epithelial form
[63]. The pharmacological inhibition of LSD1 using NCD38 significantly reduces
cell viability and neurosphere formation and induces apoptosis of glioma stem cells
(GSCs) with little effect on differentiated cells [64]. In preclinical studies using
orthotopic models, NCD38 significantly reduces GSC-driven tumor progression and
improves mouse survival. Mechanistic studies showed that NCD38 causes apoptosis
of GSCs by inducing the activation of the unfolded protein response pathway.
Thus, NCD38 and its derivatives are considered candidates for anticancer agents
as well as tools for probing the biology of LSD1. Currently, IMG-7289, an NCD38
mimetic, is being evaluated in a phase 1/2 clinical trial for the treatment of AML
and MDS (http://www.imagobio.com/imago-biosciences-doses-first-patients-inphase-12-study-of-img-7289-in-myelofibrosis/).
GlaxoSmithKline and Oryzon Genomics discovered potent and selective LSD1
inhibitors GSK2879552 and ORY-1001, respectively (Fig. 2) [65, 66]. GSK2879552
and ORY-1001 exhibit antileukemia activity and are currently undergoing clinical
trials for AML treatment. In addition, screening for cancer cell lines revealed that
small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition by PCPA analogs,
including GSK2879552 [65]. GSK2879552 exhibits DNA hypomethylation in
SCLC lines, suggesting that DNA hypomethylation can be used as a predictive
biomarker of LSD1 inhibitory activity.
In addition, Oryzon Genomics developed LSD1/MAO-B inhibitor ORY-2001.
ORY-2001 prevents the development of memory deficit in SAMP8 mice through the
induction of neuronal plasticity and the reduction of neuroinflammation [49]. Currently, ORY-2001 is being evaluated in a phase 1 clinical trial for the treatment of
Alzheimer’s disease.
Vianello et al. reported a novel PCPA derivative 1 (Fig. 2) as a potent inhibitor of
LSD1 [67]. PCPA derivative 1 strongly inhibits the clonogenic potential of acute
leukemia cell lines. Furthermore, compound 1 exhibits in vivo efficacy after oral
administration, inducing a 62% increase in survival in a mouse leukemia model.
Mai and co-workers identified hybrid LSD1/JmjC-domain containing histone
lysine demethylase inhibitors by coupling the skeleton of PCPA, an LSD1 inhibitor,
with 4-carboxy-4-carbomethoxy-2,2-bipyridine or 5-carboxy-8-hydroxyquinoline,
two 2-oxoglutarate competitive templates developed for JmjC inhibition [68]. The
hybrid compounds were validated as potential antitumor agents in cells. Compounds
2 and 3 (Fig. 2) caused growth arrest and substantial apoptosis in LNCaP prostate
and HCT116 colon cancer cells with an increase in H3K4 and H3K9 methylation
levels in the cells.
210
T. Suzuki