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Poseltinib (HM71224; LY3337641; HM-71224; LY-3337641) is a covalent/irreversible BTK (Bruton's tyrosine kinase) tyrosine kinase inhibitor with the potential for the treatment of rheumatoid arthritis. Poseltinib acts by irreversibly binding to the cysteine 481 residue in the active site of BTK and thus inhibiting Btk with an IC50 of 1.95 nM.
| ln Vitro |
In B cells, poseltinib (0.1–100 nM, 30 min) suppresses FcR and BCR signaling [1]. At dosages activated in activated Ramos B cells, poseltinib (1-1000 nM, 1 h) suppresses human monocyte production of interleukin (IL)-6, tumor factor (TNF)-alpha, and primary human B cells. The inhibition of human monocytogenes by IL-1β results in the inhibition of Btk's phosphorylation and that of its downstream components, including PLCγ2. In PBMCs, poseltinib (30 μM, 15 min) suppresses the phosphorylation of BTK, AKT, and PLCγ2 [3].
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| ln Vivo |
Poseltinib (3–30 mg/kg, lateral, once daily, from 18–40 weeks) inhibits BTK, which lowers B cell hyperactivity and attenuates lupus erythematosus (SLE) and lupus nephritis (LN) in mice. Poseltinib (1–30 mg/kg, lateral, once daily during the day) was created to alleviate experimental arthritis in mice [2].
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: B Cell Tested Concentrations: Nucleated cells form osteoclasts[2]. 0.1-100 nM Incubation Duration: 30 minutes Experimental Results: Blocks the autophosphorylation of BTK and the phosphorylation of PLCγ2, with an IC50 value less than 10 nM. Reduces TNF-α and IL-6 production in a dose-dependent manner. |
| Animal Protocol |
Animal/Disease Models: MRL/lpr mouse and NZB/W F1 mouse model [1]. ]
Doses: 3-30 mg/kg Route of Administration: Oral Experimental Results: Reduce spleen weight and prevent progression of skin lesions. Improves kidney damage and inflammation and improves survival. |
| References |
[1]. Kim YY, et al. HM71224, a selective Bruton's tyrosine kinase inhibitor, attenuates the development of murine lupus. Arthritis Res Ther. 2017 Sep 26;19(1):211.
[2]. Park JK, et al. HM71224, a novel Bruton's tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis. Arthritis Res Ther. 2016 Apr 18;18:91. [3]. Byun JY, et al. Target modulation and pharmacokinetics/pharmacodynamics translation of the BTK inhibitor poseltinib for model-informed phase II dose selection. Sci Rep. 2021 Sep 21;11(1):18671. |
| Molecular Formula |
C26H26N6O3
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|---|---|
| Molecular Weight |
470.533
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| Exact Mass |
470.2066
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| CAS # |
1353552-97-2
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| SMILES |
O1C([H])=C([H])C2=C1C(=NC(=N2)N([H])C1C([H])=C([H])C(=C([H])C=1[H])N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])OC1=C([H])C([H])=C([H])C(=C1[H])N([H])C(C([H])=C([H])[H])=O
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| Synonyms |
HM-71224 LY3337641HM 71224 LY 3337641PoseltinibHM71224 LY-3337641
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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 : ~100 mg/mL (~212.53 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 7.5 mg/mL (15.94 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 75.0 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. Solubility in Formulation 2: ≥ 7.5 mg/mL (15.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 75.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1253 mL | 10.6263 mL | 21.2526 mL | |
| 5 mM | 0.4251 mL | 2.1253 mL | 4.2505 mL | |
| 10 mM | 0.2125 mL | 1.0626 mL | 2.1253 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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