MRTX9768

• CAT Number: I032790
• CAS Number: 2629314-68-5
• Molecular Formula: C24H17FN6O
• Molecular Weight: 424.43
• Purity: ≥95%
• Synonyms: 2-[4-[4-(aminomethyl)-1-oxo-2H-phthalazin-6-yl]-2-methylpyrazol-3-yl]-3-fluoronaphthalene-1-carbonitrile
• 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: CN1C(=C(C=N1)C2=CC3=C(C=C2)C(=O)NN=C3CN)C4=C(C5=CC=CC=C5C=C4F)C#N

MRTX9768 is a potent, selective, orally active, first-in-class PRMT5-MTA complex inhibitor[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].?
MRTX9768 (0-250 nM) results in LU99 SDMA inhibition maintaining after 3-hr drug treatment followed by 4-day washout (exhibiting tight binding and prolonged PRMT5?MTA occupancy)[3].
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].

Reference

[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.

[2]. Yingqing Chen, et al. Targeting protein arginine methyltransferase 5 in cancers: Roles, inhibitors and mechanisms. Biomed Pharmacother. 2021 Oct 4;144:112252.
 [Content Brief]

[3]. Matthew A. Marx, et al. Fragment-based discovery of MRTX9768, a synthetic lethal- based inhibitor designed to bind the PRMT5•MTA complex and selectively target MTAPDEL tumors. AACR ANNUAL MEETING 2021:APRIL 10-15, 2021 AND MAY 17-21, 2021.