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Purity: ≥98%
Onametostat (JNJ-64619178; JNJ64619178) is a novel, potent, selective and pseudo-irreversible PRMT5 (protein arginine methyltransferase 5) inhibitor with potential anticancer activity. It inhibits PRMT5 with an IC50 of 0.14 nM. As an important epigenetics related enzyme, protein arginine methyltransferase 5 (PRMT5) has been confirmed as an anticancer therapeutic target in recent years. Among all the reported PRMT5 inhibitors, two small molecules (GSK-3326595 and JNJ-64619178) are currently being assessed in clinical trial.
| Targets |
PRMT5 (protein arginine methyltransferase 5, IC50 = 0.14 nM)
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|---|---|
| ln Vitro |
In an α-irreversible mode of action, onametostat binds simultaneously to the protein substrate pocket of the PRMT5/MEP50 complex and S-adenosylmethionine (SAM). On cell proliferation, onametostat has strong and wide-ranging inhibitory effects [1].
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| ln Vivo |
The surface onametostat successfully blocks the dimethylation of SMD1/3 proteins, which are part of the splicing machinery and direct substrates of methylosomes, in a number of non-small cell lung cancer and small cell lung cancer tumor xenograft models [1].
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| Enzyme Assay |
PRMT5 Inhibitory Assay Effects of the purchased compounds on methyltransferase activity of PRMT5:MEP50 were evaluated by using Alpha linked immunosorbent assay (LISA) as we previously described. [2]
JNJ-64619178 binds simultaneously to the SAM- and protein substrate- binding pockets of the PRMT5/MEP50 complex with a pseudo-irreversible mode-of-action. Chemical proteomics, methylomics and RNA-sequencing analyses of PRMT5 inhibitor treated cell line samples support the current biological understanding of PRMT5 as a regulator of alternative splicing events.[1] |
| Cell Assay |
In Vitro Proliferative Effects Assay [2]
RPMI1640 medium supplemented with 10% fetal bovine serum (per ML medium), and 1% penicillin/streptomycin (per ML medium) was used to culture Jeko-1 and MV4-11 cells. Cell culture conditions were 37°C under 5% CO2. Then the treated (4 or dimethyl sulfoxide (DMSO)) cells were plated into 24-well plate with the density of 1 × 105 cells per well for growing four days. Subsequently, viable cell number was determined through the Cell Titer-Glo Luminescent Cell Viability assays as we previously reported,16) and then translated into cell viability. Graphpad Prism 5.0 was employed to fit the IC50 values from the cell viability vs. concentration curves that were determined from at least three concentration-independence assays. Western Blotting[2] Jeko-1 cells were incubated with 4 or DMSO (control) with different concentrations for four days. Then cells were lysed in 100 µL of total lysis buffer. After 5 min incubation at room temperature (r.t.), sodium dodecyl sulfate (SDS) was added to the cell lysates. Total cell lysates were resolved in 4–12% SDS-polyacrylamide gel electrophoresis (PAGE) and transferred in for 1.5 h (80 V) onto polyvinylidene difluoride (PVDF) membrane. Afterward, blots were blocked for 1 h in blocking buffer (5% nonfat milk in 0.1% Tween 20 phosphate buffered saline (PBS)) and incubated with primary antibodies (anti-H4R3me2s (symmetric) in blocking buffer overnight at 4°C. The next day, after being washed five times with PBST (0.1% Tween 20 PBS), the blots were incubated with secondary antibody (HRP conjugated) for 1 h at r.t. Finally, the bands are read on the ChemiScope3400 imaging system. JNJ-64619178 showed potent and broad inhibition of cellular growth, observed in several cell line panels that represent diverse cancer histologies. Ongoing investigations will explore the potential synthetic lethal correlation between PRMT5 inhibition and cancer driver pathways, including those addicted to altered splicing.[1] |
| Animal Protocol |
Oral administration of JNJ-64619178 resulted in efficient inhibition of di-methylation of SMD1/3 proteins, components of the splicing machinery and direct substrates of the methylosome, in several human NSCLC and SCLC cancer mouse xenograft models. JNJ-64619178 demonstrated dose-dependent tumor growth inhibition and regression in several human NSCLC and SCLC cancer mouse xenograft models with sustained blockage of tumor re-growth after dosing cessation.
In summary, JNJ-64619178 has a favorable pre-clinical profile supporting clinical testing in patients with lung cancer and other malignancies.[1]
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| References |
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| Additional Infomation |
Onametostat is an orally available small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), with potential antiproliferative and antineoplastic activities. Upon oral administration,onametostat selectively targets and irreversibly binds to the S-adenosylmethionine (SAM)- and substrate-binding pockets of the PRMT5/methylosome protein 50 (MEP50) complex, and inhibits its function. By inhibiting its methyltransferase activity, levels of both monomethylated and dimethylated arginine residues in histones H2A, H3 and H4 are decreased. This modulates the expression of genes involved in several cellular processes, including cellular proliferation. This may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation, which may lead to decreased growth of rapidly proliferating cells, including cancer cells. PRMT5, a type II methyltransferase that catalyzes the formation of both omega-N monomethylarginine (MMA) and symmetric dimethylarginine (sDMA) on histones and a variety of other protein substrates involved in signal transduction and cellular transcription, is overexpressed in several neoplasms. Elevated levels are associated with decreased patient survival.
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| Molecular Formula |
C22H23BRN6O2
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|---|---|
| Molecular Weight |
483.3610
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| Exact Mass |
482.11
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| Elemental Analysis |
C, 54.67; H, 4.80; Br, 16.53; N, 17.39; O, 6.62
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| CAS # |
2086772-26-9
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| PubChem CID |
126637809
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| Appearance |
Off-white to light yellow solid
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
31
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| Complexity |
631
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C1[C@@H]([C@H]([C@H]([C@@H]1N2C=CC3=C(N=CN=C32)N)O)O)CCC4=CC5=NC(=C(C=C5C=C4)Br)N
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| InChi Key |
DBSMLQTUDJVICQ-CJODITQLSA-N
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| InChi Code |
InChI=1S/C22H23BrN6O2/c23-15-8-12-3-1-11(7-16(12)28-21(15)25)2-4-13-9-17(19(31)18(13)30)29-6-5-14-20(24)26-10-27-22(14)29/h1,3,5-8,10,13,17-19,30-31H,2,4,9H2,(H2,25,28)(H2,24,26,27)/t13-,17+,18+,19-/m0/s1
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| Chemical Name |
(1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol
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| Synonyms |
JNJ64619178; JNJ 64619178; JNJ-64619178.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~258.61 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.30 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 20.8 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: ≥ 2.08 mg/mL (4.30 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 20.8 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: ≥ 2.08 mg/mL (4.30 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 | 2.0689 mL | 10.3443 mL | 20.6885 mL | |
| 5 mM | 0.4138 mL | 2.0689 mL | 4.1377 mL | |
| 10 mM | 0.2069 mL | 1.0344 mL | 2.0689 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.
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