| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Other Sizes |
| Targets |
Bruton's tyrosine kinase (BTK) ; DC50 = 0.34 nM; CRBN
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|---|---|
| ln Vitro |
- NX-5948 is a potent degrader of BTK in primary human B cells with a DC50 of 0.34 nM. It also inhibits B cell receptor (BCR) signaling. [1]
- Proteomic analysis shows NX-5948 is highly selective for BTK degradation, with limited activity toward the CRBN neo-substrate Aiolos (DC50 > 10 µM). [1] - NX-5948 induces degradation of wild-type and mutant forms of BTK in B-cells at sub-nanomolar potencies. [2] |
| ln Vivo |
- In vivo, once daily oral administration of NX-5948 in mice and cynomolgus monkeys demonstrated potent degradation of BTK in circulating B cells. [1]
- NX-5948 demonstrated significant anti-inflammatory activity and resulted in improvement of clinical symptoms in a mouse collagen-induced arthritis (CIA) model. [1] - NX-5948 exhibits potent tumor growth inhibition in TMD8 xenograft models that contain either wild-type BTK or BTK-resistant mutations. [2] |
| Cell Assay |
- BTK Degradation Assay: Robust degradation of BTK was observed by flow cytometry in primary human B cells after 4-hour treatment with NX-5948. The half-maximal degradation concentration (DC50) was determined to be 0.34 nM. [1]
- Proteomic Analysis: The selectivity of NX-5948 for BTK degradation was assessed via proteomic analysis, which demonstrated minimal off-target degradation, particularly showing a DC50 > 10 µM for the CRBN neo-substrate Aiolos. [1] - Assessment of BTK Degradation in Patients: In a Phase 1a trial, BTK expression in patients' blood samples was measured to evaluate degradation. Rapid, robust, and sustained BTK degradation was observed across all patients, irrespective of baseline BTK level, tumor type, or NX-5948 dose. [2] |
| Animal Protocol |
- Mouse Collagen-Induced Arthritis (CIA) Model: The anti-inflammatory activity of NX-5948 was evaluated in a mouse CIA model. The compound was administered orally once daily. The study showed significant anti-inflammatory activity and improvement in clinical symptoms. [1]
- In Vivo Pharmacodynamic Study in Mice and Cynomolgus Monkeys: To assess BTK degradation in vivo, NX-5948 was administered orally once daily to mice and cynomolgus monkeys. Potent degradation of BTK in circulating B cells was subsequently observed. [1] - TMD8 Xenograft Model: The anti-tumor efficacy of NX-5948 was evaluated in TMD8 xenograft models, which include both wild-type BTK and BTK-resistant mutations. The study demonstrated potent tumor growth inhibition. [2] |
| ADME/Pharmacokinetics |
- In Humans (Phase 1a Trial): NX-5948 exhibits dose-dependent pharmacokinetics (PK) with a half-life of approximately 24 hours, supporting once-daily dosing. [2]
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| Toxicity/Toxicokinetics |
- In Humans (Phase 1a Trial): NX-5948 was well tolerated with no dose-limiting toxicities (DLTs). There were no treatment-emergent adverse events (TEAEs) resulting in drug discontinuation or dose reduction, and no drug-related Grade ≥3 TEAEs or related serious adverse events. The most common TEAEs were purpura/contusion (57.1%, all below grade 3), nausea (35.7%), and thrombocytopenia (35.7%). No atrial fibrillation/flutter or hypertension was reported. [2]
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| References | |
| Additional Infomation |
- Background & Mechanism: NX-5948 is a chimeric targeting molecule (CTM) that engages the E3 ligase cereblon (CRBN) to promote the selective degradation of BTK. It is an orally administered small molecule. [1]
- Clinical Development: Preclinical animal models support the clinical development of NX-5948 for treating autoimmune diseases. [1] A Phase 1a/b first-in-human trial (NX-5948-301) is being conducted in patients with relapsed/refractory B cell malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). [2] - Clinical Activity (Phase 1a): In heavily pre-treated patients, early signs of clinical activity were observed. Of three evaluable CLL patients receiving the lowest dose of 50 mg, one confirmed partial response (PR) and two patients had stable disease (SD) at the 8-week assessment. [2] |
| Molecular Formula |
C42H54N12O5
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|---|---|
| Molecular Weight |
806.955567836761
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| Exact Mass |
806.434
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| Elemental Analysis |
C, 62.51; H, 6.75; N, 20.83; O, 9.91
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| CAS # |
2649400-34-8
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| Related CAS # |
2649400-33-7
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| PubChem CID |
156464216
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| Appearance |
Off-white to yellow solid powder
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| LogP |
2.6
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
59
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| Complexity |
1500
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C1(C(N)=O)=NC=C(N2CCC[C@@H](N3C(=O)N(C)CC3)C2)N=C1NC1=CC=C(C2CCN(CC3CCN(C4=CC=C(C(N[C@H]5CCC(=O)NC5=O)=O)N=C4)CC3)CC2)C=C1
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| InChi Key |
HPTPDBYCFHFWJG-CWTKIQHKSA-N
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| InChi Code |
InChI=1S/C42H54N12O5/c1-50-21-22-54(42(50)59)32-3-2-16-53(26-32)35-24-45-37(38(43)56)39(48-35)46-30-6-4-28(5-7-30)29-14-17-51(18-15-29)25-27-12-19-52(20-13-27)31-8-9-33(44-23-31)40(57)47-34-10-11-36(55)49-41(34)58/h4-9,23-24,27,29,32,34H,2-3,10-22,25-26H2,1H3,(H2,43,56)(H,46,48)(H,47,57)(H,49,55,58)/t32-,34+/m1/s1
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| Chemical Name |
3-[4-[1-[[1-[6-[[(3S)-2,6-dioxopiperidin-3-yl]carbamoyl]pyridin-3-yl]piperidin-4-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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| Synonyms |
NX-5948; Bexobrutideg; NX 5948; 2649400-34-8; BTK-IN-24; HVD6HGW6JD; NX5948;
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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: 50 mg/mL (61.96 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.33 mg/mL (4.13 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 33.3 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: ≥ 3.33 mg/mL (4.13 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 33.3 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: ≥ 3.33 mg/mL (4.13 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 | 1.2392 mL | 6.1961 mL | 12.3922 mL | |
| 5 mM | 0.2478 mL | 1.2392 mL | 2.4784 mL | |
| 10 mM | 0.1239 mL | 0.6196 mL | 1.2392 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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