ChemicalBook CAS DataBase List 1616392-22-3

1616392-22-3

Name	6-[(1-acetylpiperidin-4-yl)amino]-N-[(2S)-2-hydroxy-3-(1,2,3,4-tetrahydroisoquinolin-2-yl)propyl]pyrimidine-4-carboxamide
CAS	1616392-22-3
Molecular Formula	C24H32N6O3
MDL Number	MFCD29991177
Molecular Weight	452.55
MOL File	1616392-22-3.mol

Chemical Properties

Boiling point	760.3±60.0 °C(Predicted)
density	1.275±0.06 g/cm3(Predicted)
storage temp.	Keep in dark place,Inert atmosphere,2-8°C
solubility	Soluble in DMSO (up to 20 mg/ml).
form	solid
pka	12.44±0.46(Predicted)
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

Safety Data

Symbol(GHS)	GHS07
Signal word	Warning
Hazard statements	H302-H315-H319-H335
Precautionary statements	P261-P264-P270-P271-P280-P301+P312-P330-P302+P352-P321-P304+P340-P305+P351+P338-P332+P313-P362+P364-P337+P313-P403+P233-P405-P501

Hazard Information

Description

GSK3326595 (1616395-22-3) is a potent (IC50?= 6.2nM), selective (>4000-fold over 20 other methyltransferases), SAM uncompetitive, peptide competitive inhibitor of PRMT5.1?PRMT5 inhibition activated the p53 pathway?via?induction of alternative splicing of MDM4 leading to a potent anti-proliferative response both?in vitro?and?in 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.2?Currently 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 9?weeks) increased hepatic triglyceride levels without affecting atherosclerosis in LDL receptor knockout mice^[3]. GSK3326595 (25-50 mg/kg, Oral, once a day for 2?weeks) 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

storage

Store at -20°C

References

1) Gerhart?et al.?(2018),?Activation of the p53-MDM4 regulatory axis defines the anti-tumor response to PRMT5 inhibition through its role in regulating cellular splicing; Sci. Rep.?8?9711 2) AbuHammad?et al.?(2019),?Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma; Proc. Natl. Acad. Sci. USA?116?179909 3) NCT02783300

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