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(±)-Zanubrutinib is a racemic mixture of Zanubrutinib (formerly known as BGB-3111) which is a novel, highly selective, second generation BTK inhibitor, currently under clinical investigation in hematological cancers. BGB-3111 showed nanomolar BTK inhibition activity in both biochemical and cellular assays. BGB-3111 effectively suppressed BCR aggregation-induced BTK autophosphorylation, obstructed downstream PLC-γ2 signaling, and slowed down the growth of multiple MCL and DLBCL cell lines. Against a panel of kinases, including ITK, BGB-3111 exhibited far more restricted off-target activities in contrast to ibrutinib. BGB-3111 was at least ten times less effective than ibrutinib in inhibiting rituximab-induced ADCC, which is consistent with its weak ITK inhibition activity. However, ibrutinib significantly inhibited rituximab-induced NK cell IFN-γ secretion and in vitro cytotoxicity on mantle cell lymphoma cells.
| Targets |
BTK/Bruton tyrosine kinase
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|---|---|
| ln Vitro |
(±)-Zanubrutinib ((±)-BGB-3111) exhibits nanomolar Btk inhibition activity in both biochemical and cellular assays. (±)-Zanubrutinib inhibits BCR aggregation-triggered Btk autophosphorylation, blocks downstream PLC-γ2 signaling, and potently inhibits cell proliferation in a number of MCL and DLBCL cell lines. When it comes to a panel of kinases, including ITK, (±)-Zanubrutinib exhibits far more limited off-target activities when compared to PCI-32765[1].
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| ln Vivo |
(±)-Zanubrutinib produces dose-dependent anti-tumor effects against REC-1 MCL xenografts that are injected into mice's tail veins and engrafted subcutaneously or systemically. in the xenografts placed beneath the skin. An initial 14-day rat toxicity study reveals that (±)-Zanubrutinib is highly well tolerated, and doses up to 250 mg/kg/day do not result in the maximal tolerated dose (MTD) being reached[1].
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| Enzyme Assay |
In both biochemical and cellular assays, BGB-3111 demonstrated nanomolar BTK inhibition activity. In several MCL and DLBCL cell lines, BGB-3111 inhibited BCR aggregation-triggered BTK autophosphorylation, blocked downstream PLC-γ2 signaling, and potently inhibited cell proliferation. In comparison with ibrutinib, BGB-3111 showed much more restricted off-target activities against a panel of kinases, including ITK. While ibrutinib significantly inhibited rituximab-induced NK cell IFN-γ secretion and in vitro cytotoxicity on mantle cell lymphoma cells, BGB-3111 was at least 10-fold weaker than ibrutinib in inhibiting rituximab induced ADCC, consistent with its weak ITK inhibition activity.[1]
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| Animal Protocol |
In mouse BTK occupancy assays, treatment with BGB-3111 resulted in a dose-dependent BTK occupancy and showed about 3-fold more potency than ibrutinib in target organs, including PBMC and spleen. BGB-3111 induced dose-dependent anti-tumor effects against REC-1 MCL xenografts engrafted either subcutaneously or systemically via tail vein injection in mice. In the subcutaneous xenografts, BGB-3111 at 2.5 mg/kg BID showed similar activity as ibrutinib at 50 mg/kg QD, its clinical relevant dose. In the systemic model, the median survival of BGB-3111 25 mg/kg BID group was significantly longer than those of both ibrutinib 50 mg/kg QD and BID groups. In an ABC-subtype DLBCL (TMD-8) subcutaneous xenograft model, BGB-3111 also demonstrated better anti-tumor activity than ibrutinib. Preliminary 14-day toxicity study in rats showed that BGB-3111 was very well tolerated and maximal tolerate dose (MTD) was not reached when it was dosed up to 250mg/kg/day.[1]
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| References | |
| Additional Infomation |
See also: Zanubrutinib (annotation moved to).
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| Molecular Formula |
C27H29N5O3
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|---|---|---|
| Molecular Weight |
471.56
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| Exact Mass |
471.227
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| Elemental Analysis |
C, 68.77; H, 6.20; N, 14.85; O, 10.18
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| CAS # |
1633350-06-7
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| Related CAS # |
Zanubrutinib;1691249-45-2;(R)-Zanubrutinib;1691249-44-1;Zanubrutinib-d5; 1633350-06-7 (racemic); 1691249-45-2 (S-isomer); 1691249-44-1 (R-isomer)
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| PubChem CID |
135905454
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| Appearance |
White to light yellow solid
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
713.4±60.0 °C at 760 mmHg
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| Flash Point |
385.2±32.9 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.680
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| LogP |
3.64
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
756
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C([H])=C([H])[H])N1C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])C1([H])C([H])([H])C([H])([H])N([H])C2=C(C(N([H])[H])=O)C(C3C([H])=C([H])C(=C([H])C=3[H])OC3C([H])=C([H])C([H])=C([H])C=3[H])=NN12
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| InChi Key |
RNOAOAWBMHREKO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H29N5O3/c1-2-23(33)31-16-13-18(14-17-31)22-12-15-29-27-24(26(28)34)25(30-32(22)27)19-8-10-21(11-9-19)35-20-6-4-3-5-7-20/h2-11,18,22,29H,1,12-17H2,(H2,28,34)
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| Chemical Name |
2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.41 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 (4.41 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 (4.41 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 | 2.1206 mL | 10.6031 mL | 21.2062 mL | |
| 5 mM | 0.4241 mL | 2.1206 mL | 4.2412 mL | |
| 10 mM | 0.2121 mL | 1.0603 mL | 2.1206 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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