1-Naphthalenecarbonitrile, 2-[4-[4-(aminomethyl)-1,2-dihydro-1-oxo-6-phthalazinyl]-1-methyl-1H-pyrazol-5-yl]-3-fluoro-

Product Name1-Naphthalenecarbonitrile, 2-[4-[4-(aminomethyl)-1,2-dihydro-1-oxo-6-phthalazinyl]-1-methyl-1H-pyrazol-5-yl]-3-fluoro-
CAS2629314-68-5
MFC24H17FN6O
MW424.43
EINECS
MOL File2629314-68-5.mol

Chemical Properties

Density	1.44±0.1 g/cm3(Predicted)
storage temp.	-20°C, protect from light
solubility	DMSO : 30 mg/mL (70.68 mM; ultrasonic and warming and heat to 60°C)
pka	11.36±0.40(Predicted)
form	Solid
color	White to light brown
InChI	InChI=1S/C24H17FN6O/c1-31-23(22-18(10-26)15-5-3-2-4-13(15)9-20(22)25)19(12-28-31)14-6-7-16-17(8-14)21(11-27)29-30-24(16)32/h2-9,12H,11,27H2,1H3,(H,30,32)
InChIKey	BPTYWAYMKBEXES-UHFFFAOYSA-N
SMILES	C1(C#N)=C2C(C=CC=C2)=CC(F)=C1C1N(C)N=CC=1C1C=CC2=C(C=1)C(CN)=NNC2=O

Usage And Synthesis

Uses

MRTX9768 is a potent, selective, orally active, first-in-class PRMT5-MTA complex inhibitor[1].

Biological Activity

MRTX9768 is a potent, orally active PRMT5 inhibitor. MRTX9768 is a synthetic lethal-based inhibitor designed to bind the PRMT5-MTA complex and selectively target MTAP/CDKN2A-deleted tumors[1]. MRTX9768 inhibits SDMA and cell proliferation in HCT116 MTAP-del cells (SDMA IC50 3 nM; prolif. IC50 11 nM) with marked selectivity over HCT116 MTAP-WT cells (SDMA IC50 544 nM; prolif. IC50 861 nM)[1]. In xenograft studies, oral administration of MRTX9768 demonstrates dose-dependent inhibition of SDMA in MTAP-del tumors[1].

in vivo

In xenograft studies, oral administration of MRTX9768 demonstrates dose-dependent inhibition of SDMA in MTAP-del tumors, with less SDMA modulation observed in bone marrow^[1].
MRTX9768 selectively targets MTAP/CDKN2A-deleted tumors (such as glioblastoma)^[1]^[2].
MRTX9768 (PO dose 30 mg/kg in CD-1 mouse and beagle dog, 10 mg/kg in cynomolgus monkey) has a favorable ADME profile (>50% bioavailability in mice and dogs, moderate to high clearance, No changes in RBC parameters when administered well above efficacious concentrations (1000 mg/kg))^[3].
MRTX9768 (100 mg/kg, orally, BID, 6/21 days) results in SDMA inhibition maintaining 3 days after dosing is stopped^[3].

IC 50

PRMT5

References

[1]. Christopher R. et al. Fragment based discovery of MRTX9768, a synthetic lethal-based inhibitor designed to bind the PRMT5-MTA complex and selectively target MTAP/CDKN2A-deleted tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB003.

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