ChemicalBook Product Catalog Biochemical Engineering Biochemical Reagents Agonist Inhibitors GSK-3326595

GSK-3326595

Product NameGSK-3326595
CAS1616392-22-3
MFC24H32N6O3
MW452.55
EINECS
MOL File1616392-22-3.mol

Chemical Properties

Boiling point	760.3±60.0 °C(Predicted)
Density	1.275±0.06 g/cm3(Predicted)
storage temp.	under inert gas (nitrogen or Argon) at 2–8 °C
solubility	Soluble in DMSO (up to 20 mg/ml).
pka	12.44±0.46(Predicted)
form	solid
color	Off-white
Stability	Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.
InChIKey	JLCCNYVTIWRPIZ-NRFANRHFSA-N
SMILES	C1=NC(NC2CCN(C(C)=O)CC2)=CC(C(NC[C@H](O)CN2CCC3=C(C2)C=CC=C3)=O)=N1

Usage And Synthesis

Description

GSK3326595 (1616395-22-3) is a potent (IC50= 6.2nM), selective (>4000-fold over 20 other methyltransferases), SAM uncompetitive, peptide competitive inhibitor of PRMT5.1PRMT5 inhibition activated the p53 pathwayviainduction of alternative splicing of MDM4 leading to a potent anti-proliferative response bothin vitroandin vivo. Combination therapy with palbociclib (CDK4/6 inhibitor, Focus Cat.# 10-4760) and GSK3326595 lead to increased efficacy of palbociclib in treating native and resistant models of melanoma via regulation of the PRMT5-MDM4 axis.2Currently in clinical trials.3

Uses

GSK-3326595 is a protein arginine methyltransferase 5(PRMT5) inhibitor under clinical trial.

in vivo

GSK3326595 (5 mg/kg, Intraperitoneal injection, three times a week for 9weeks) increased hepatic triglyceride levels without affecting atherosclerosis in LDL receptor knockout mice^[3]. GSK3326595 (25-50 mg/kg, Oral, once a day for 2weeks) enhances the efficacy of anti-programed cell death protein 1 (PD-1) immune checkpoint therapy (ICT) in hepatocellular carcinoma (HCC) in myelocytomatosis transgene turned on (MYC-ON) mice^[5].

Animal Model:	LDL receptor knockout mice^[3]
Dosage:	5 mg/kg
Administration:	Intraperitoneal injection (i.p.)
Result:	Did not alter atherosclerosis susceptibility. Increased hepatic triglyceride levels without changing the hyperlipidemia extent. Activated genes involved in fatty acid acquisition.

Animal Model:	myelocytomatosis transgene turned on mice^[5]
Dosage:	25 mg/kg, 50 mg/kg
Administration:	Oral
Result:	Significantly suppressed tumor growth at 50 mg/kg. Showed better therapeutic efficacy at 25 mg/kg.

IC 50

PRMT5; CDK4; CDK6

References

[1] SARAH V GERHART. Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing.[J]. Scientific Reports, 2018: 9711. DOI:10.1038/s41598-018-28002-y
[2] SHATHA ABUHAMMAD. Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 1: 17990-18000. DOI:10.1073/pnas.1901323116

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