ORY-1001 is a highly potent and selective KDM1A inhibitor with IC50 value of 18nM. It engaged
enzymatically active KDM1A in THP1 cells with an EC50 of 0.63nM and 0.55 nM after 24 and 96 hr of treatment, respectively. Inhibition of KDM1A by ORY-1001 induced H3K4me2 accumulation on KDM1A target genes. The ten genes that were most potently induced after 96 hr were VCAN, S100A8, S100A9, S100A12, LYZ, ANXA2, ANXA8, OSBPL11, KCKN13, and FCRLA. Genes significantly downregulated by ORY-1001 include genes de-regulated in MLL-translocated AML (CCL5, RHOBTB3, HOXA9, HOXA10, HOXA11) as well as genes identified as direct targets of MLL-AF9 or MLL-AF4 (HOXA10, CDK6, SLC38A1, HIVEP2, ARHGAP25, TAPT1, REEP3, PPP3R2, and FLT3) and KIT. ORY-1001 potently reduced the colony-forming potential in a variety of AML cell lines, with MLL-translocated AML cell lines such as THP1 (MLL-AF9) and MV(4;11) (MLL-AF4) being the most sensitive, and induced blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibited potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduced growth of an AML xenograft model, and extends survival in a mouse PDX model of T cell acute leukemia at dose of 0.0125mg/kg[2].
作用机制
ORY-1001 could rapidly and covalently bind to the FAD cofactor in KDM1A in a manner analogous to tranylcypromine.[2]
ORY-1001 did not significantly affect normal cell proliferation
Front Pharmacol. 2018 Dec 4;9:1411.
NCI-H510A
0.002 to 2000 nM
10 days
Assessed the impact on cell viability, showing that ORY-1001 exhibited subnanomolar antiproliferative activity in NCI-H510A cells.
ACS Pharmacol Transl Sci. 2021 Nov 12;4(6):1818-1834.
MV(4;11)
2000, 200, 20, and 2 nM
24 hours
Assessed LSD1 target engagement, showing that ORY-1001 achieved high LSD1 target engagement at all concentrations tested.
ACS Pharmacol Transl Sci. 2021 Nov 12;4(6):1818-1834.
A549 cells
50 nM
24 hours
ORY-1001 inhibits KDM1A, leading to accumulation of H3K9 methylation and loss of H3K9 acetylation
Epigenetics Chromatin. 2023 May 13;16(1):18.
U2OS cells
50 nM
24 hours
ORY-1001 inhibits KDM1A, leading to accumulation of H3K9 methylation and loss of H3K9 acetylation
Epigenetics Chromatin. 2023 May 13;16(1):18.
FHSC04
1 nM
48 hours
ORY-1001 treatment led to changes in NOTCH1, REST, and ASCL1 transcription and protein expression, with increased cell death.
Sci Signal. 2019 Feb 5;12(567):eaau2922.
BT-474 cells
10 µM
48 hours
To evaluate the effect of iadademstat on SOX2 enhancer-driven transcriptional activation in BT-474 cells, results showed that iadademstat dose-dependently suppressed the transcriptional activation of SOX2
Aging (Albany NY). 2020 Mar 18;12(6):4794-4814.
MGC-803
5 µM
5 days
Induced accumulation of H3K4me1/2 and H3K9me1/2, inhibited gastric cancer cell migration
Front Pharmacol. 2021 Apr 15;12:640949.
BGC-823
5 µM
5 days
Induced accumulation of H3K4me1/2 and H3K9me1/2, inhibited gastric cancer cell migration
Front Pharmacol. 2021 Apr 15;12:640949.
MDA-MB-436 cells
3.98 µM (IC50)
6 days
To evaluate the effect of iadademstat on mammosphere formation in MDA-MB-436 cells, results showed that iadademstat dose-dependently reduced the number of mammospheres
Aging (Albany NY). 2020 Mar 18;12(6):4794-4814.
TF-1a
0.002 to 2000 nM
96 hours
Assessed the impact on cell viability, showing that ORY-1001 exhibited subnanomolar antileukemic activity in TF-1a cells.
ACS Pharmacol Transl Sci. 2021 Nov 12;4(6):1818-1834.
THP-1
0.02 to 2000 nM
96 hours
Assessed the induction of CD11b protein levels, showing that ORY-1001 significantly induced CD11b expression in THP-1 cells.
ACS Pharmacol Transl Sci. 2021 Nov 12;4(6):1818-1834.
NCI-H510A
10 nM
96 hours
ORY-1001 treatment resulted in 1400 differentially expressed genes (FDR<0.05), with enrichment in NOTCH pathway genes and decreased expression of ASCL1.
Sci Signal. 2019 Feb 5;12(567):eaau2922.
ORY-1001 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG mice
SCLC PDX models
Oral
400μg/kg
Once weekly for 21 days
ORY-1001 showed tumor inhibitory effects in all six of the ASCL1-positive PDX models tested, with complete and durable tumor regression observed in the FHSC04 model.
Sci Signal. 2019 Feb 5;12(567):eaau2922.
C57BL/6 mice
TC-1 subcutaneous xenograft model
Intraperitoneal injection
50 mg/kg
Three times per week for 3-4 weeks
To evaluate the inhibitory effect of ORY-1001 combined with anti-CD47/PD-L1 monoclonal antibodies on tumor growth. The results showed that the combination of ORY-1001 and anti-CD47/PD-L1 monoclonal antibodies significantly inhibited tumor growth more effectively than a single blockade strategy.
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