MRTX9768 HCl is a potent, selective, orally bioactive, first-in-class inhibitor of the PRMT5-MTA complex.

Physicochemical Properties

Molecular Formula	C24H18CLFN6O
Molecular Weight	460.89
Related CAS #	MRTX9768;2629314-68-5
Appearance	White to off-white solid powder
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	PRMT5•MTA[1]
ln Vitro	In HCT116 MTAP-del cells (SDMA IC50 3 nM; prolif. IC50 11 nM), MRTX9768 selectively reduces SDMA and cell proliferation compared to HCT116 MTAP-WT cells (SDMA IC50 544 nM; prolif. IC50 861 nM)[1]. (0-250 nM) causes LU99 SDMA inhibition to be maintained following a 3-hour drug treatment and a 4-day washout period (showing tight binding and extended PRMT5 MTA occupancy)[3].
ln Vivo	Oral treatment of MRTX9768 causes dose-dependent suppression of SDMA in MTAP-del tumors in xenograft trials; SDMA modulation in bone marrow is less[1]. Glioblastoma and other MTAP/CDKN2A-deleted cancers are specifically targeted by MRTX9768[1] [2]. With a good ADME profile (>50% bioavailability in mice and dogs, moderate to high clearance, and no changes in RBC parameters when delivered much above effective concentrations (1000 mg/kg), MRTX9768 (PO dosage 30 mg/kg in CD-1 mouse and beagle dog, 10 mg/kg in cynomolgus monkey)[3]. Three days after stopping the dosage, MRTX9768 (100 mg/kg, orally, BID, 6/21 days) causes SDMA inhibition to remain[3].
References	[1]. Abstract LB003: Fragment based discovery of MRTX9768, a synthetic lethal-based inhibitor designed to bind the PRMT5-MTA complex and selectively target MTAP/CDKN2A-deleted tumors. AACR Annual Meeting 2021; April 10-15, 2021 and. [2]. Targeting protein arginine methyltransferase 5 in cancers: Roles, inhibitors and mechanisms. Biomed Pharmacother. 2021 Oct 4;144:112252. [3]. 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.

Solubility Data

Solubility (In Vitro)

H2O :~40 mg/mL (~86.79 mM) DMSO :~19 mg/mL (~41.22 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 4.5 mg/mL (9.76 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 45.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 4.5 mg/mL (9.76 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 45.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 4.5 mg/mL (9.76 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 45.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1697 mL	10.8486 mL	21.6972 mL
	5 mM	0.4339 mL	2.1697 mL	4.3394 mL
	10 mM	0.2170 mL	1.0849 mL	2.1697 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.