The human decapping scavenger enzyme (DcpS), belonging to the HIT family of pyrophosphatases, catalyzes residual cap hydrolysis following mRNA degradation and prevents accumulation of intermediates that might interfere with translation and normal processing of mRNAs[1]. RG3039 displays a potent DcpS inhibitory activity with an IC50 of 4.2 ± 0.13 nM and an IC90 of 40 nM in the DcpS inhibition assay. It shows good brain penetration with high brain-to-plasma partitioning and a half-life of ∼10 h. RG3039-treated (oral gavage with 20 mg/kg) SMA (spinal muscular atrophy) mice had a median survival that was 38% greater than vehicle-treated SMA mice[2].
RG3039 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HA1800
8 µM
48 hours
To evaluate the toxicity of RG3039 on normal astrocytes, results showed that RG3039 had low toxicity on normal cells.
J Transl Med. 2024 Sep 30;22(1):880
U118
6 µM
48 hours
To evaluate the effect of RG3039 on GBM cell proliferation and apoptosis, results showed that RG3039 significantly inhibited cell proliferation and induced apoptosis.
J Transl Med. 2024 Sep 30;22(1):880
A172
6 µM
48 hours
To evaluate the effect of RG3039 on GBM cell proliferation and apoptosis, results showed that RG3039 significantly inhibited cell proliferation and induced apoptosis.
J Transl Med. 2024 Sep 30;22(1):880
U251
6 µM
48 hours
To evaluate the effect of RG3039 on GBM cell proliferation and apoptosis, results showed that RG3039 significantly inhibited cell proliferation and induced apoptosis.
J Transl Med. 2024 Sep 30;22(1):880
U87
6 µM
48 hours
To evaluate the effect of RG3039 on GBM cell proliferation and apoptosis, results showed that RG3039 significantly inhibited cell proliferation and induced apoptosis.
J Transl Med. 2024 Sep 30;22(1):880
HEK293T cells
100 nM
48 hours
Validate RG3039 effects on specific RNAs (e.g., HS370762 and BC011766), confirming DcpS-dependency
RNA. 2015 Jul;21(7):1306-12
SH-SY5Y neuroblastoma cells
100 nM
48 hours
Examine global mRNA levels upon DcpS decapping inhibition, revealing changes in 222 RNAs
RNA. 2015 Jul;21(7):1306-12
CALM/AF10 cells
1 µM
6 hours and 10 hours
To assess the effect of RG3039 on pre-mRNA splicing in AML cells. RG3039 treatment increased pre-mRNA mis-splicing in AML cells, particularly at the first exon or the first intron.
Cancer Cell. 2018 Mar 12;33(3):386-400. e5
MOLM-13 cells
1 µM
6 hours and 10 hours
To evaluate the anti-proliferative and differentiation-inducing effects of RG3039 on AML cells. RG3039 treatment resulted in slowed proliferation, cell cycle arrest, increased apoptosis, and differentiation toward the myelo/monocytic lineage.
Cancer Cell. 2018 Mar 12;33(3):386-400. e5
RG3039 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Taiwanese SMA mouse model and 2B/2SMA mouse model
Oral
10 mg/kg, 20 mg/kg, 2.5 mg/kg
Once daily for 8 days
RG3039 can extend survival and improve function in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/2SMA mice), and positively impacts neuromuscular pathologies. In 2B/2SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosing began at P4, highlighting the importance of early intervention.
Hum Mol Genet. 2013 Oct 15;22(20):4084-101
Mice
Severe SMA mouse model
Intraperitoneal injection
10 mg/kg/day
Daily from postnatal day 1 (P1) until death
To evaluate the effects of RG3039 on disease outcomes in SMA mice, results showed that treatment significantly improved survival, weight, and motor function, enhanced motor neuron and neuromuscular junction synaptic connectivity and function, and increased muscle size.
Hum Mol Genet. 2013 Oct 15;22(20):4074-83
BALB/c nude mice
Orthotopic GBM mouse model
Intraperitoneal injection
20 mg/kg
Once daily until the endpoint of observation
To evaluate the inhibitory effect of RG3039 on GBM tumor growth in vivo, results showed that RG3039 significantly inhibited tumor growth and prolonged mouse survival.
J Transl Med. 2024 Sep 30;22(1):880
Mice
CALM/AF10 or MLL/AF9 leukemia model
Intraperitoneal injection
20 mg/kg
Once daily for 14 days
To evaluate the anti-leukemia effects of RG3039 in vivo. RG3039 treatment significantly reduced the burden of AML cells in the blood and bone marrow and prolonged the survival of mice.
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