NRX-0492
Based on 1 Customer Validation
NRX-0492 is an orally active BTK PROTAC degrader, with a binding IC50 of 1.2 nM for both wild-type BTK and BTKT474I, and 2.7 nM for BTKC481S, and exhibits cellular DC50 values of 0.1 nM and 0.2 nM against wild-type BTK and BTKC481S, respectively. NRX-0492 catalyzes the ubiquitination and proteasomal degradation of wild-type and drug-resistant mutant BTK by recruiting the CRBN E3 ubiquitin ligase complex. NRX-0492 inhibits the BCR signaling pathway and its downstream NF-κB/MYC transcriptional program, achieves rapid and sustained degradation in primary CLL cells, and exhibits extremely low cytotoxicity. NRX-0492 degrades BTK, inhibits tumor cell proliferation and activation, and significantly suppresses tumor growth in xenograft models. NRX-0492 can be used in research related to chronic lymphocytic leukemia and diffuse large B-cell lymphoma.
(Pink: Btk ligand (HY-49421); Blue: Cereblon ligand (HY-W087383); Black: linker (HY-60263)).
Para uso exclusivo en investigación. No vendemos a pacientes.
- Pureza : 98.30%
- No. CAS: 2416130-57-7
- Fòrmula: C43H51N11O6
- Peso molecular:817.94
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Almacenamiento:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Actividad biológica
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Chemical Information
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Solvente y solubilidad
- Pureza y Documentación
- Referencias
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Help & FAQs
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Actividad biológica
Descripciòn
IC50 & Target
IC50 values of 1.2 nM (wild-type BTK), 2.7 nM (C481S mutant BTK), and 1.2 nM (T474I mutant BTK)
In Vitro
NRX-0492 (4 h) potently and rapidly degrades wild-type BTK and BTKC481S mutants in primary chronic lymphocytic leukemia (CLL) cells from all tested risk groups; it exhibits an ED50 of 0.18 nM and an ED90 of 0.5 nM at 4 h, does not induce significant cytotoxicity, and maintains BTK inhibitory activity for several days after drug washout[1].
NRX-0492 (0.05-10 nM; 4 h) induces proteasome- and cereblon-dependent degradation of wild-type BTK (DC50 0.1 nM, DC90 0.3 nM) and BTKC481S mutant (DC50 0.2 nM, DC90 0.5 nM) in TMD8 cells[2].
NRX-0492 (50 nM; 6 h) mediates highly selective degradation of BTK in TMD8 cells[2].
NRX-0492 (0.0001-2 nM; 4 hours) induces rapid and sustained degradation of BTK in unmutated primary chronic lymphocytic leukemia (CLL), mutated CLL, 13q-deleted CLL, and 17p-deleted CLL cells at subnanomolar concentrations (DC50 ≤0.2 nM, DC90 ≤0.5 nM), with its activity persisting for at least 24 hours after washout[2].
NRX-0492 (0.03-5 nM; 24 h) effectively degrades the BTKC481S mutant BTK in primary ibrutinib-resistant chronic lymphocytic leukemia (CLL) cells, with DC50 values of 0.4 nM and 0.9 nM, whereas wild-type BTK bound to ibrutinib remains unaffected[2].
NRX-0492 (0.0098-10 nM; 6 h) potently degrades BTK in OCI-Ly10 cells, with a DC50 of 0.3 nM and a maximum degradation rate of 98.3%[4].
NRX-0492 (72 h) potently inhibits the proliferation of diffuse large B-cell lymphoma cells. After 72 h of treatment, the IC50 values are 0.1 nM for OCI-Ly10 (BTKWT), 4.3 nM for TMD-8 (BTKWT), 0.3 nM for OCI-Ly10 (BTKC481S), and 3.8 nM for TMD-8 (BTKC481S)[4].
NRX-0492 (1 h) binds tightly to purified wild-type BTK, BTKC481S mutant, and BTKT474I mutant proteins, with corresponding IC50 values of 1.2 nM, 2.7 nM, and 1.2 nM, respectively; its IC50 value for binding to CRBN is 9 nM[2].
NRX-0492 binds to wild-type BTK with a docking score of -11.9 kcal/mol; re-docking verification confirms the reliability of this docking protocol, with an RMSD of 1.01 Å[3].
NRX-0492 binds to BTK with the BTKC481S mutation, with a docking score of -10.6 kcal/mol[3].
NRX-0492 (150 ns) forms a stable complex with wild-type BTK during the 150 ns simulation, with high binding affinity, and its MM/PBSA ΔGbinding is -48.8 kcal/mol[3].
NRX-0492 (150 ns) forms a stable complex with C481S-mutated BTK during simulation, with an MM/PBSA binding free energy ΔGbinding of -45.8 kcal/mol[3].
NRX-0492 (1 μM; 60 min) exhibits low metabolic stability, with 6.3% remaining in human liver microsomes and 28.0% remaining in mouse liver microsomes after incubation at 1 μM for 60 minutes[4].
NRX-0492 potently inhibits the kinase activities of BTKWT (IC50 = 1.2 nM), BTKC481S (IC50 = 2.7 nM) and BTKT474I (IC50 = 1.2 nM)[4].
NRX-0492 (2 nM; 18 hours) effectively inhibits BCR-dependent signaling pathways, transcriptional programs and chemokine secretion in primary CLL cells, with activity comparable to that of ibrutinib[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Ibrutinib-resistant primary CLL cells
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Concentration:0, 0.03, 0.06, 0.125, 0.25, 0.5, 1, 2 and 5 μM
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Incubation Time:24 h
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Result:Effectively degraded BTKC481S mutant BTK in primary ibrutinib-resistant chronic lymphocytic leukemia (CLL) cells, with DC50 values of 0.4 nM and 0.9 nM, whereas wild-type BTK complexed with ibrutinib was protected from degradation.
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Cell Line:Ibrutinib-resistant primary CLL cells
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Concentration:0.05, 0.1, 0.2, 0.5, 2 and 4 nM
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Incubation Time:4h
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Result:Inhibition of CRL4CRBN or the proteasome precluded BTK degradation, and excess CRBN or BTK ligand prevented degradation, confirming that the compound's activity was proteasome-dependent and required direct engagement with CRBN and BTK.
TMD8 cells expressing wild-type or C481S mutant BTK were treated with increasing concentrations of the compound for 4 hours. Degradation of wild-type and C481S mutant BTK was achieved at DC50 values of 0.1 nM and 0.2 nM, and DC90 values of 0.3 nM and 0.5 nM, respectively.
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Cell Line:Ibrutinib-resistant primary CLL cells
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Concentration:0.001, 0.003, 0.0075, 0.015, 0.031, 0.062, 0.125, 0.25, 0.5 and 2
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Incubation Time:4h
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Result:Degradation of both wild-type and C481S mutant BTK was achieved at DC50 values of 0.1 nM and 0.2 nM, and DC90 values of 0.3 nM and 0.5 nM, respectively.
Pretreatment median BTK levels were approximately 60% higher in unmutated CLL than in mutated CLL, but BTK degradation was equally achieved in both subsets and in samples with deletion 13q or 17p.
PBMCs from 8 patients with CLL were treated with 0.5 nM of the compound for 4 hours. After drug washout, BTK levels continued to decline, reaching their lowest level 24 hours after washout, with only minimal recovery observed by 96 hours.
Parmacokinetics
In Vivo
NRX-0492 (0.2 mg/mL; p.o.; continuous dosing; day 1 to day 20) induces complete BTK degradation and inhibits proliferation in xenografts of ibrutinib-resistant CLL harboring BTKC481S mutation[2].
NRX-0492 (30 mg/kg; p.o.; daily; 20 days) achieves 89.4% tumor growth inhibition in a TMD-8 diffuse large B-cell lymphoma xenograft mouse model with minimal toxicity[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NOD/SCID/IL2Rgnull (NSG) female mice (6-8 weeks old) was injected intraperitoneally (i.p.) with 20 × 106 primary CLL cells and intravenously (i.v.) with 40 × 106 primary CLL cells (total 60 × 106 cells per mouse) from treatment-naïve CLL patients.[2]
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Dosage:30 mg/kg (single dose); 0.2 mg/mL (continuous dosing)
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Administration:p.o.; single dose (day 1); continuous dosing (day 1 to day 21)
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Result:Significantly reduced BTK mean fluorescent intensity (MFI) relative to vehicle controls in peripheral blood CLL cells on day 8.
Significantly lowered BTK MFI in peripheral blood and spleen on day 22.
Reduced the percentage of Ki67+ proliferating CLL cells in peripheral blood on day 8 and day 22, and in spleen on day 22.
Significantly reduced the percentage of CD69+ activated CLL cells in peripheral blood and spleen on day 22.
Significantly reduced spleen CLL tumor burden.
Consistently promoted BTK degradation in blood and spleen, reduced Ki67+ CLL cell fractions, and decreased spleen tumor burden across 4 additional patient-derived xenograft cohorts.
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Animal Model:NOD/SCID/IL2Rgnull (NSG) female mice (6-8 weeks old) was injected intraperitoneally (i.p.) with 20 × 106 primary CLL cells and intravenously (i.v.) with 40 × 106 primary CLL cells (total 60 × 106 cells per mouse) from a CLL patient who had progressed on ibrutinib with BTKC481S mutation (cancer cell fraction: 88% C481S mutant).[2]
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Dosage:0.2 mg/mL
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Administration:p.o.; continuous dosing; day 1 to day 21
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Result:Significantly reduced BTK MFI in peripheral blood CLL cells relative to vehicle controls on day 8.
Reduced the percentage of Ki67+ proliferating CLL cells on day 8.
Resulted in undetectable BTK in spleen-infiltrating CLL cells via Western blot on day 20, indicating complete degradation of both wild-type and C481S mutant BTK.
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Animal Model:NOD-SCID female mice (6-8 weeks) were implanted subcutaneously into the right flank with 1 × 107 TMD-8 cells in 100 μL. The tumors were allowed to grow until they reached a volume of 100-300 mm3[4]
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Dosage:30 mg/kg
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Administration:p.o.; daily; 20 days
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Result:Achieved a tumor growth inhibition rate (TGI) of 89.4%.
Reduced mean final tumor weight to 0.137 g.
Caused minimal animal weight loss or other signs of toxicity.
Chemical Information
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No. CAS 2416130-57-7
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Appearance Solid
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Peso molecular 817.94
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Fòrmula C43H51N11O6
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Color Light yellow to yellow
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SMILES
NC(C1=C(N=C(N2CCC[C@@H](N3CCN(C)C3=O)C2)C=N1)NC(C=C4)=CC=C4C(CC5)CCN5C[C@@H](C6)CCN6C7=CC=C(C(C(N8C9C(NC(CC9)=O)=O)=O)=C7)C8=O)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Solvente y solubilidad
In Vitro:
DMSO : 200 mg/mL (244.52 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Pureza y Documentación
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Ficha de datos (287 KB)
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SDS (254 KB)
- English - EN (254 KB)
- Français - FR (254 KB)
- Deutsch - DE (254 KB)
- Norwegian - NO (254 KB)
- Español - ES (254 KB)
- Swedish - SV (254 KB)
- Italian - IT (254 KB)
- Korean - KR (254 KB)
- Portuguese - PT (254 KB)
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Instrucciones de manejo (2659 KB)
Referencias
[2]. Zhang D, et al. NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts. Blood. 2023 Mar 30;141(13):1584-1596. [Content Brief]
[4]. Ren J, et al. Discovery of as a Potent and Orally Bioavailable BTK PROTAC Degrader Incorporating a Novel Benzisoxazole-Based CRBN Ligand for the Treatment of B-Cell Malignancies. Journal of medicinal chemistry. 2025 Aug 14;68(15):15960-15979. [Content Brief]
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
|---|---|---|---|---|---|
| DMSO | 1 mM | 1.2226 mL | 6.1129 mL | 12.2258 mL | 30.5646 mL |
| 5 mM | 0.2445 mL | 1.2226 mL | 2.4452 mL | 6.1129 mL | |
| 10 mM | 0.1223 mL | 0.6113 mL | 1.2226 mL | 3.0565 mL | |
| 15 mM | 0.0815 mL | 0.4075 mL | 0.8151 mL | 2.0376 mL | |
| 20 mM | 0.0611 mL | 0.3056 mL | 0.6113 mL | 1.5282 mL | |
| 25 mM | 0.0489 mL | 0.2445 mL | 0.4890 mL | 1.2226 mL | |
| 30 mM | 0.0408 mL | 0.2038 mL | 0.4075 mL | 1.0188 mL | |
| 40 mM | 0.0306 mL | 0.1528 mL | 0.3056 mL | 0.7641 mL | |
| 50 mM | 0.0245 mL | 0.1223 mL | 0.2445 mL | 0.6113 mL | |
| 60 mM | 0.0204 mL | 0.1019 mL | 0.2038 mL | 0.5094 mL | |
| 80 mM | 0.0153 mL | 0.0764 mL | 0.1528 mL | 0.3821 mL | |
| 100 mM | 0.0122 mL | 0.0611 mL | 0.1223 mL | 0.3056 mL |
NRX-0492 Related Classifications
HY-153357 Related Classifications
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