| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| Other Sizes |
| Targets |
PRMT5•MTA[1]
MRTX9768 hydrochloride targets the PRMT5-MTA complex. Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme that symmetrically dimethylates arginine residues on histones and other proteins. In MTAP-deleted cancers, MTA accumulates and binds PRMT5. MRTX9768 binds the PRMT5-MTA complex, selectively inhibiting PRMT5 activity in MTAP-deleted tumors while sparing normal cells. |
|---|---|
| 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].
MRTX9768 inhibits SDMA (symmetric dimethylarginine) and cell proliferation in HCT116 MTAP-del cells with an SDMA IC50 of 3 nM and a proliferation IC50 also in the low nanomolar range. It is a highly potent and selective inhibitor of the PRMT5-MTA complex, designed to avoid broader PRMT5 inhibition that can cause on-target toxicity in normal cells. |
| 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].
MRTX9768 hydrochloride is orally bioavailable and exhibits potent anti-tumor activity in preclinical xenograft models of MTAP-deleted cancers. It is a synthetic lethal-based inhibitor that selectively kills MTAP/CDKN2A-deleted tumor cells without affecting normal cells. Specific in vivo efficacy data includes significant tumor growth inhibition in mouse models, though detailed numbers are not provided in the literature. |
| Enzyme Assay |
A standard PRMT5 enzyme activity assay involves incubating recombinant PRMT5-MTA complex (10-50 nM) with a biotinylated histone H4 peptide substrate (1-10 microM) and SAM (S-adenosylmethionine, 1-10 microM) in assay buffer (50 mM Tris-HCl, pH 8.5, 50 mM NaCl, 1 mM DTT) with varying concentrations of MRTX9768 hydrochloride (0.1-1000 nM). After 30-60 minutes at 30degC, methylation is detected using a specific antibody against symmetric dimethylated arginine (anti-sdme) in a time-resolved FRET (TR-FRET) or ELISA format. IC50 values for SDMA inhibition are calculated.
|
| Cell Assay |
A standard cellular protocol involves treating HCT116 MTAP-del cells (or other MTAP-deleted cancer cell lines) with MRTX9768 hydrochloride at varying concentrations (0.1-1000 nM) for 48-72 hours. Cells are lysed and analyzed by Western blotting using an anti-sdme antibody to measure global symmetric dimethylarginine levels as a pharmacodynamic marker. Cell proliferation is assessed by MTT or CellTiter-Glo assays. The SDMA IC50 is typically 3 nM, and the proliferation IC50 is similarly low.
|
| Animal Protocol |
A standard in vivo protocol involves establishing subcutaneous xenografts of MTAP-deleted cancer cells (e.g., HCT116 MTAP-del) in nude mice. Once tumors reach a volume of 100-200 mm3, mice are randomized and treated with MRTX9768 hydrochloride by oral gavage (e.g., 1-50 mg/kg) daily for 2-4 weeks. Tumor volume is measured twice weekly. Pharmacodynamic assessment involves collecting tumor tissue at endpoint and measuring sdme levels by immunohistochemistry or Western blot.
|
| ADME/Pharmacokinetics |
MRTX9768 hydrochloride is orally bioavailable with good absorption following oral administration. Its molecular formula and weight are derived from the free base (C24H17FN5O, MW 424.43) plus HCl. For in vitro use, it is soluble in DMSO (~50 mg/mL). For oral administration, it can be formulated in 0.5% methylcellulose or other vehicles. The compound is stable as a powder at -20degC for up to 3 years.
|
| Toxicity/Toxicokinetics |
Specific toxicological data for MRTX9768 hydrochloride is limited. As a PRMT5 inhibitor, on-target toxicity includes anemia and thrombocytopenia due to PRMT5's role in hematopoiesis. However, the PRMT5-MTA complex selectivity of MRTX9768 is designed to minimize these effects by sparing normal cells without MTA accumulation. Preclinical toxicology studies have shown a favorable safety profile compared to non-selective PRMT5 inhibitors.
|
| References |
|
| Additional Infomation |
MRTX9768 hydrochloride is a research-grade first-in-class PRMT5-MTA complex inhibitor. It has been developed by Mirati Therapeutics (now part of Bristol Myers Squibb) for the treatment of MTAP/CDKN2A-deleted tumors, including certain pancreatic, lung, and gastric cancers. MTAP deletion occurs in approximately 15% of all cancers. This compound has entered clinical development but is not yet approved by the FDA. This product is for laboratory research use only.
|
| 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)
|
| 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. View More
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. |
| 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
