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| Targets |
Bruton's tyrosine kinase (BTK). NRX-0492 is a small-molecule BTK inhibitor that forms a covalent bond with a specific cysteine residue in the BTK active site. It is designed to be selective and to overcome the C481S mutation, which confers resistance to first-generation BTK inhibitors like ibrutinib.
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| ln Vitro |
NRX-0492 is a potent and selective BTK inhibitor. In cell-free assays, it shows high affinity for wild-type BTK and clinically relevant mutations, including the C481S resistance mutant. In cellular assays using B-cell lymphoma lines, it effectively blocks BTK phosphorylation and downstream signaling (e.g., PLCgamma2, ERK), leading to potent anti-proliferative effects.
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| ln Vivo |
NRX-0492 demonstrates robust in vivo efficacy in rodent xenograft models of B-cell lymphoma. It is orally bioavailable and achieves high systemic exposures, leading to significant tumor growth inhibition and regression in models resistant to first-generation BTK inhibitors. This confirms its potential to overcome acquired resistance.
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| Enzyme Assay |
Cell-free BTK kinase assays are performed using recombinant wild-type and mutant (e.g., C481S) BTK enzymes. The compound is incubated with the enzyme and a peptide substrate in the presence of ATP. Activity is measured by a luminescence-based ADP detection kit. IC50 values are calculated from the dose-response curves.
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| Cell Assay |
BTK-dependent B-cell lymphoma cell lines (e.g., TMD-8, REC-1) are seeded in 96-well plates and treated with serial dilutions of NRX-0492 for 48-72 hours. Cell viability is measured using the CellTiter-Glo reagent. The level of BTK phosphorylation (p-BTK) is measured by Western blot or an ELISA to assess target engagement.
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| Animal Protocol |
Female BALB/c nude mice are inoculated subcutaneously with TMD-8 or REC-1 cells. When tumors are established, mice are randomized and treated orally with NRX-0492 once daily. Tumor volumes are measured with calipers twice weekly. Tumor tissues are collected for pharmacokinetic and pharmacodynamic analysis, including measuring p-BTK levels.
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| ADME/Pharmacokinetics |
NRX-0492 is an orally bioavailable small-molecule BTK inhibitor. Its physicochemical properties are optimized for oral absorption, allowing for high plasma exposure. It is expected to have a moderate half-life, allowing for once- or twice-daily dosing. Its pharmacokinetics have been characterized in preclinical species but not fully disclosed.
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| Toxicity/Toxicokinetics |
No specific toxicity data are publicly detailed. As a BTK inhibitor, its therapeutic window is defined by on-target effects in healthy B cells. Covalent BTK inhibitors can have off-target liabilities due to promiscuous cysteine binding. NRX-0492 is designed to be highly selective, which may reduce such toxicities.
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| References | |
| Additional Infomation |
Other information: NRX-0492 is a preclinical research compound discovered by Nurix Therapeutics. It represents a next-generation BTK inhibitor in a class known as "Targeted Protein Degradation" or "Covalent BTK inhibitors". It is not yet an FDA-approved drug and is available only for research. Its CAS number is 2416130-57-7.
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| Molecular Formula |
C43H51N11O6
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|---|---|
| Molecular Weight |
817.935148477554
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| Exact Mass |
817.402
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| CAS # |
2416130-57-7
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| PubChem CID |
146559024
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.7
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
60
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| Complexity |
1650
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CN1CCN(C1=O)[C@@H]2CCCN(C2)C3=CN=C(C(=N3)NC4=CC=C(C=C4)C5CCN(CC5)C[C@@H]6CCN(C6)C7=CC8=C(C=C7)C(=O)N(C8=O)C9CCC(=O)NC9=O)C(=O)N
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| InChi Key |
WFDYOAWNEOGIPM-NJZOVTIDSA-N
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| InChi Code |
InChI=1S/C43H51N11O6/c1-49-19-20-53(43(49)60)31-3-2-15-52(25-31)35-22-45-37(38(44)56)39(47-35)46-29-6-4-27(5-7-29)28-13-16-50(17-14-28)23-26-12-18-51(24-26)30-8-9-32-33(21-30)42(59)54(41(32)58)34-10-11-36(55)48-40(34)57/h4-9,21-22,26,28,31,34H,2-3,10-20,23-25H2,1H3,(H2,44,56)(H,46,47)(H,48,55,57)/t26-,31+,34?/m0/s1
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| Chemical Name |
3-[4-[1-[[(3S)-1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]piperidin-4-yl]anilino]-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide
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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: 200 mg/mL (244.52 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2226 mL | 6.1129 mL | 12.2258 mL | |
| 5 mM | 0.2445 mL | 1.2226 mL | 2.4452 mL | |
| 10 mM | 0.1223 mL | 0.6113 mL | 1.2226 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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