Details
Stereochemistry | ACHIRAL |
Molecular Formula | C21H23Cl2N5O |
Molecular Weight | 432.346 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NC1=NC2=C(C(N)=N1)C(OCC3CCN(CC4=C(Cl)C=CC=C4Cl)CC3)=CC=C2
InChI
InChIKey=MNLHFGXIUJNDAF-UHFFFAOYSA-N
InChI=1S/C21H23Cl2N5O/c22-15-3-1-4-16(23)14(15)11-28-9-7-13(8-10-28)12-29-18-6-2-5-17-19(18)20(24)27-21(25)26-17/h1-6,13H,7-12H2,(H4,24,25,26,27)
Molecular Formula | C21H23Cl2N5O |
Molecular Weight | 432.346 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
RG3039, also known as PF-06687859, is the first small molecule developed specifically for treatment of Spinal muscular atrophy (SMA). This drug is used in SMA patients that have reached early stage clinical trials. It was shown that RG3039 improved survival, function and motor unit pathologies in SMA mouse models. It is known, that RG3039 is a potent inhibitor of the mRNA decapping scavenger enzyme (DcpS). DcpS is a nuclear shuttling protein that binds and hydrolyzes the m(7)GpppN mRNA cap structure and a modulator of RNA metabolism. Therefore, DcpS represents an intrigueing therapeutic target for modulating gene expression by a small molecule. The exact therapeutic mechanism remains unknown.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23727836
Curator's Comment: Known to be CNS penetrant in mouse. Human data not available
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: Q96C86 Gene ID: 28960.0 Gene Symbol: DCPS Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/28257199 |
0.069 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23727836
in mice: Mice received intraperitoneal (i.p.) injections starting on post natal day 1 (P1) defined as the day of birth. All treated litters were culled at P4 to a total of six pups. RG3039 was dissolved in distilled water (or saline in Ko laboratory) at appropriate concentrations for 2.5 µl volume/gram injection volume. Mice treated with RG3039 at 10 mg/kg/day showed increased weights and survival, which were not further increased by the 20 mg/kg dose.
Route of Administration:
Intraperitoneal
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23727836
To verify the ability of RG3039 to inhibit DcpS, it was examined DcpS enzyme activity in protein extracts isolated from a P10 SMA mouse brain treated in vitro with various doses of the drug. DcpS activity. Mouse brains were homogenized in lysis buffer (PBS, pH 7.4, 1% BSA, 0.1% IGEPAL CA-630 with protease and phosphatase inhibitors). For the DcpS enzyme decapping assay, 20 µg of tissue extract was mixed with 3 µm of biotinylated CAP substrate m7GpppA(N6) in the decapping buffer (50 mm Tris, pH 7.9, 100 mm MgCl2, 150 mm (NH4)2SO4) with a 10 µl total reaction volume. The reaction was terminated by adding 10 µl of 10 µm RG3039 to the reaction mixture. The resulting enzymatic reaction product, biotinylated ADP, was quantified using ELISA. As expected, RG3039 robustly inhibited DcpS enzyme activity in a dose-dependent manner with an IC50 = 3.4 nm.
Substance Class |
Chemical
Created
by
admin
on
Edited
Fri Dec 15 19:48:00 GMT 2023
by
admin
on
Fri Dec 15 19:48:00 GMT 2023
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Record UNII |
KSV93L7URW
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Record Status |
Validated (UNII)
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Record Version |
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FDA ORPHAN DRUG |
289509
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KSV93L7URW
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100000181829
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