Cat. No.: HY-153357

NRX-0492

Customer Review

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 BTK^T474I, and 2.7 nM for BTK^C481S. 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)).

For research use only. We do not sell to patients.

Purity: 98.30%
CAS No.: 2416130-57-7
Formula: C₄₃H₅₁N₁₁O₆
Molecular Weight:817.94

Storage:

Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month

NRX-0492 Chemical Structure

CAS No.: 2416130-57-7

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Fluorescent Dye

Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Biological Activity
- Description
- IC₅₀ & Target
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
Solvent & Solubility
- In Vitro
Purity & Documentation
References
Help & FAQs
Classifications
Bioz

Biological Activity

Description

NRX-0492 is an orally active BTK PROTAC degrader, with a binding IC₅₀ of 1.2 nM for both wild-type BTK and BTK^T474I, and 2.7 nM for BTK^C481S. 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^[1]^[2]^[3]^[4]. (Pink: Btk ligand (HY-49421); Blue: Cereblon ligand (HY-W087383); Black: linker (HY-60263)).

IC₅₀ & Target

IC₅₀ values of 1.2 nM (wild-type BTK), 2.7 nM (C481S mutant BTK), and 1.2 nM (T474I mutant BTK)

All PROTACs Isoforms :

All NF-κB Isoforms :

In Vitro

NRX-0492 (4 h) potently and rapidly degrades wild-type BTK and BTK^C481S 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 BTK^C481S 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 BTK^C481S 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 (BTK^WT), 4.3 nM for TMD-8 (BTK^WT), 0.3 nM for OCI-Ly10 (BTK^C481S), and 3.8 nM for TMD-8 (BTK^C481S)^[4].
NRX-0492 (1 h) binds tightly to purified wild-type BTK, BTK^C481S mutant, and BTK^T474I 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 BTK^C481S 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 ΔG_binding 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 ΔG_binding 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 BTK^WT (IC₅₀ = 1.2 nM), BTK^C481S (IC₅₀ = 2.7 nM) and BTK^T474I (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.

Western Blot Analysis^[2]

Cell Line:

Ibrutinib-resistant primary CLL cells
Concentration:

0, 0.03, 0.06, 0.125, 0.25, 0.5, 1, 2 and 5 μM
Incubation Time:

24 h
Result:

Effectively degraded BTK^C481S 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.

Western Blot Analysis^[2]

Cell Line:

Ibrutinib-resistant primary CLL cells
Concentration:

0.05, 0.1, 0.2, 0.5, 2 and 4 nM
Incubation Time:

4h
Result:

Inhibition of CRL4^CRBN 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.

Western Blot Analysis^[2]

Cell Line:

Ibrutinib-resistant primary CLL cells
Concentration:

0.001, 0.003, 0.0075, 0.015, 0.031, 0.062, 0.125, 0.25, 0.5 and 2
Incubation Time:

4h
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

Species	Dose	Route	V_d	CL	AUC_0-∞	T_1/2	C_max	Bioavailability
Mice^[5]	1 mg/kg	i.v.	1.2 L/kg	0.5 L/h/kg	/	/	/	/
Mice^[5]	10 mg/kg	p.o.	/	/	3652 ng·h/mL	1.9 h	404 ng/mL	17.3 %

In Vivo

NRX-0492 (0.2 mg/mL-30 mg/kg; p.o.; single dose, continuous dosing; 1-22 days) induces robust BTK degradation in CLL patient-derived xenografts, significantly inhibiting CLL cell proliferation, activation, and tumor burden^[2].
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 BTK^C481S 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.

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]
Dosage:

30 mg/kg (single dose); 0.2 mg/mL (continuous dosing)
Administration:

p.o.; single dose (day 1); continuous dosing (day 1 to day 21)
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.

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 BTK^C481S mutation (cancer cell fraction: 88% C481S mutant).^[2]
Dosage:

0.2 mg/mL
Administration:

p.o.; continuous dosing; day 1 to day 21
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.

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]
Dosage:

30 mg/kg
Administration:

p.o.; daily; 20 days
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

CAS No. 2416130-57-7
Appearance Solid
Molecular Weight 817.94
Formula C₄₃H₅₁N₁₁O₆
Color Light yellow to yellow
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
Shipping

Room temperature in continental US; may vary elsewhere.

Storage

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	6 months
	-20°C	1 month

Solvent & Solubility

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)

View the Complete Stock Solution Preparation Table

Preparing Stock Solutions

View the Complete Stock Solution Preparation Table

Concentration Solvent Mass

1 mg

5 mg

10 mg

Concentration

Solvent

Mass

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

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.

Molarity Calculator

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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Purity & Documentation

Select Batch:

Purity: 99.98%

Assay: 99.98%

ee.: 99.98%

Data Sheet (287 KB)
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)
COA (2659 KB)
Elemental Analysis Report (2659 KB)
HNMR (2659 KB)
CNMR (2659 KB)
RP-HPLC (2659 KB)
NP-HPLC (2659 KB)
MS (2659 KB)
LCMS (2659 KB)
IR (2659 KB)
GC (2659 KB)
OR (2659 KB)
SDS-PAGE (2659 KB)
SEC-HPLC (2659 KB)
Other Report (2659 KB)
Handling Instructions (2659 KB)

References

[1]. Zhang D, et al. Highly potent BTK degradation induced by NRX0492 as a therapeutic strategy for CLL[J]. Blood, 2019, 134: 174.

[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]

[3]. Issahaku A R, et al. Camptothecin and its Analogues as Putative Bruton Tyrosine Kinase (BTK) Inhibitors in Cancer Therapy-Biophysical Simulations of Wild Type and C481S Mutation[J]. Journal of Cancer Biomoleculars and Therapeutics, 2024, 1(1): 59-71.

[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]

Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

Complete Stock Solution Preparation Table

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

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NRX-0492

Immunology/Inflammation Compound Library

Protein Tyrosine Kinase Compound Library

Anti-Cancer Compound Library

Covalent Screening Library

Orally Active Compound Library

Anti-Blood Cancer Compound Library

PROTAC Library

Autoimmune Disease Compound Library

Anti-Hematopathy Compound Library

Bioactive Compound Library Max

MCE Bioactive Compound Library

Covalent Screening Library Plus

Bioactive Compound Library

Protein Kinase Compound Library

High-Throughput Bioactive Compound Library

All PROTACs Isoforms

All NF-κB Isoforms

Biological Activity

Chemical Information

Solvent & Solubility

Purity & Documentation

References

Help & FAQs

Complete Stock Solution Preparation Table

NRX-0492

Immunology/Inflammation Compound Library

Protein Tyrosine Kinase Compound Library

Anti-Cancer Compound Library

Covalent Screening Library

Orally Active Compound Library

Anti-Blood Cancer Compound Library

PROTAC Library

Autoimmune Disease Compound Library

Anti-Hematopathy Compound Library

Bioactive Compound Library Max

MCE Bioactive Compound Library

Covalent Screening Library Plus

Bioactive Compound Library

Protein Kinase Compound Library

High-Throughput Bioactive Compound Library

All PROTACs Isoforms

All NF-κB Isoforms

Biological Activity

Chemical Information

Solvent & Solubility

Purity & Documentation

References

Help & FAQs

Complete Stock Solution Preparation Table

NRX-0492 Related Classifications

HY-153357 Related Classifications