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Purity: ≥98%
| Targets |
BTK/Bruton's Tyrosine Kinase
Orelabrutinib targets Bruton's tyrosine kinase (BTK), a key enzyme in the B-cell receptor (BCR) signaling pathway. BTK is essential for the proliferation, survival, and activation of B cells. By irreversibly binding to BTK, orelabrutinib inhibits BTK activity with an IC50 value of 1.6 nM, thereby blocking BCR signaling and inhibiting the growth of malignant B-cells. |
|---|---|
| ln Vitro |
Orelabrutinib has an IC50 value of 1.6 nM and effectively suppresses BTK enzymatic activity. Orelabrutinib only targets BTK with > 90% inhibition in a parallel KINOMEscan assay at 1 μM against a panel of 456 kinases, whereas ibrutinib inhibits many other kinases, such as EGFR, TEC, and BMX, indicating orelabrutinib's superior kinase selectivity.[2]
In vitro, orelabrutinib irreversibly inhibits BTK with an IC50 value of 1.6 nM. It demonstrates bioactivity by inhibiting protein phosphorylation across various cell types. In human Ramos cells, it inhibits BTK phosphorylation. It displays high selectivity at 1 μM against a panel of 456 kinases, only targeting BTK with >90% inhibition. |
| ln Vivo |
Orelabrutinib exhibits a good PK profile in preclinical PK/PD studies, with an ideal T1/2 of ~1.5–4 h, good oral bioavailability of ~20–80%, and prolonged BTK target occupancy. In the GLP toxicological investigations in rats and dogs, the higher selectivity results in an enhanced safety profile and a wide safety window.[2]
In vivo, orelabrutinib has shown antineoplastic activity. It is an orally active compound and is currently being investigated in clinical studies for the treatment of B-cell malignancies. Its irreversible binding to BTK provides sustained target inhibition. |
| Enzyme Assay |
Ibrutinib, orelabrutinib, and zanubrutinib are all Bruton's tyrosine kinase inhibitors, which have greatly improved the treatment of B-cell malignancies. In this study, an LC-MS/MS method was developed and validated for the determination of orelabrutinib, zanubrutinib, ibrutinib, and its active metabolite dihydrodiol ibrutinib in human plasma. The Ibrutinib-d5 was used as the internal standard. Pretreatment was performed using a simple protein precipitation step using acetonitrile. The ACQUITY UPLC HSS T3 column (2.1×50 mm, 1.8 μm) was used to separate the analytes, and the run time was 6.5 min. The mobile phase consisted of acetonitrile and 10 mM of ammonium formate, which contained 0.1% formic acid. The multiple reactions' monitoring transitions were selected at m/z 428.1→411.2, 472.2→455.2, 441.1→304.2, 475.2→304.2 and 446.2→309.2 respectively for orelabrutinib, zanubrutinib, ibrutinib, dihydrodiol ibrutinib and ibrutinib-d5 using positive ion electrospray ionization. The standard curves were linear, from 0.400 to 200 ng/mL for ibrutinib and dihydrodiol ibrutinib, 1.00-500 ng/mL for orelabrutinib, and 2.00-1000 ng/mL for zanubrutinib. Selectivity, the lower limit of quantitation, precision, accuracy, matrix effect, recovery, stability, and dilution integrity all met the acceptance criteria of FDA guidance. This method was used to quantify the plasma levels of orelabrutinib, zanubrutinib, ibrutinib, and dihydrodiol ibrutinib in clinical patients.Molecules
. 2023 Jan 26;28(3):1205.
Non-cellular assays for orelabrutinib involve measuring its inhibition of BTK kinase activity. These assays use recombinant BTK and a peptide substrate. The enzyme is incubated with the substrate and ATP in the presence of varying concentrations of orelabrutinib. The phosphorylation of the substrate is measured to determine the IC50 (1.6 nM). Its selectivity is confirmed by profiling against a large panel of kinases. |
| Cell Assay |
Orelabrutinib, a new oral BTK inhibitor, combined with the Bcl-2 inhibitor venetoclax, was used to confirm the antitumor effect of DHL. Cell counting kit-8 and Annexin V-FITC/PI assays were used to examine the interaction of this combined regimen on DHL cell lines and primary lymphoma cells. RNA sequencing, EdU incorporation assay, mitochondrial membrane potential assay, and western blotting were employed to explore the molecule mechanism for the cytotoxicity of orelabrutinib with or without venetoclax against DHL cell lines.
Results: In this study, orelabrutinib combined with venetoclax synergistically induced DHL cell death, as evidenced by the inhibition of cell proliferation, the induct of cell cycle arrest, and the promotion of cell apoptosis via the mitochondrial pathway. Orelabrutinib treatment alters genome-wide gene expression in DHL cells. The combined regimen decreases the expression of BTK and Mcl-1, potentially interfering with the activity and crosstalk of PI3K/AKT signaling and p38/MAPK signaling. In addition, the combination of orelabrutinib and venetoclax shows cytotoxic activity in primary B-lymphoma cells.
Conclusion: In summary, these findings reveal a novel therapy targeting BCR signaling and the Bcl-2 family for DHL patients with a poor prognosis. J Cancer Res Clin Oncol
. 2023 Aug;149(9):5513-5529.
In vitro cellular assays for orelabrutinib are conducted in B-cell lines, such as Ramos cells. Cells are treated with the compound, and BTK phosphorylation is measured by Western blot or phospho-specific ELISA. Cell proliferation is measured using MTT or CellTiter-Glo assays. The inhibition of downstream signaling pathways (e.g., PLCγ2, ERK) is also assessed. |
| Animal Protocol |
Near complete (>99%) BTK occupancy was achieved at a dose of 50 mg or higher with small inter-subject variability, and the effect was sustained for 24 hours post dosing, which is consistent with the covalent binding mode of orelabrutinib. The Cmax that required to achieve complete (>99%) BTK occupancy (EC99) is ~300 ng/mL. In summary, orelabrutinib has superior selectivity, favorable PK, prolonged PD as well as a large safety window in both preclinical and clinical phase I studies. Therefore, orelabrutinib may offer an excellent option for the treatment of B-cell malignancies in avoid of the high frequency of adverse events (diarrhea, atrial fibrillation, bleeding, etc.) observed for ibrutinib and other BTK inhibitors. Orelabrutinib is currently under investigation with multiple phase II trials in patients with B-cell malignancies.[2]
Of the 80 enrolled pts, seventy-eight pts were evaluable for response (by 31 of May 2019), the ORR was 88.5% (69/78). Among them, one patient was reported as CR, 39 pts were PR and 29 pts were PR-L. Stable disease was seen in 6/78 (7.7%). Total disease control rate is 96.2%. The median DOR was not reached, 6 months DOR rate was 89.8%. Subgroup analysis (age, disease stage, previous treatment, 17p deletion, 11q deletion, IGHV mutation) did not reveal significant differences. Conclusion: Orelabrutinib is safe and well tolerated. No significant adverse events like atrial fibrillation/flutter or secondary malignancies were reported. Orelabrutinib is efficacious to treat pts with r/r CLL/SLL. The improved safety, resulting from high target selectivity, and daily dosing regimen enable Orelabrutinib to be a valuable therapeutic choice both as monotherapy and likely in combination with other agents to treat B-cell malignancies.[1] In vivo animal experiments with orelabrutinib are conducted in mouse xenograft models of B-cell malignancies. Tumor-bearing mice are administered the compound orally, and tumor growth is monitored. Tumor tissues are harvested for analysis of BTK phosphorylation and downstream signaling. |
| ADME/Pharmacokinetics |
Systemic exposures (AUC and Cmax) were well proportional to dose, indicating good linear pharmacokinetic characteristics. The mean terminal half-life for all cohorts was approximately 4 hours. No drug accumulation was observed in plasma after repeated dosing. No significant food effect was observed when administered concurrently with a standard high-fat, high-calorie meal. [2]
Orelabrutinib is an orally active compound. It is soluble in DMSO and is typically stored as a powder at -20°C. Its pharmacokinetic properties, such as oral bioavailability and half-life, have been characterized in preclinical and clinical studies. |
| Toxicity/Toxicokinetics |
The most frequent (≥15%) adverse events of any grade (AE) included characteristic hematologic toxicities: thrombocytopenia, neutropenia, and anemia; as well as respiratory infections and purpura. No cases of atrial fibrillation or secondary malignancies were reported. The most frequent (≥10%) adverse events of any grade ≥3 included neutropenia, thrombocytopenia, and pulmonary infections. Twenty-five patients experienced at least one serious adverse event. Of these, 13 were considered to be related to orelabrutinib treatment, including decreased platelet count (3), pneumonia, fever (2 each), and herpes zoster (1 each). [1]
Orelabrutinib was well-safe and well-tolerated in healthy subjects receiving a single dose up to 400 mg or multiple doses up to 100 mg (twice daily) or 200 mg (once daily) for 14 days. All treatment-related adverse events (TEAEs) reported during the study were mild or moderate and resolved before the end of the study. Petechiae and headache were the most common treatment-related TEAEs. No dose-limiting toxicities (DLTs) were observed, and the maximum tolerated dose (MTD) was not reached. No serious TEAEs, treatment-discontinuing TEAEs, or death-causing TEAEs were reported during this study. Orelabrutinib is generally well-tolerated. Common adverse effects may include hematological toxicities, gastrointestinal disturbances, and infections. It is contraindicated in patients with known hypersensitivity. It is not approved for human therapeutic use in all regions but is in clinical development. |
| References | |
| Additional Infomation |
Orelabrutinib is being investigated in the clinical trial NCT04305197 (ICP-022 study in patients with systemic lupus erythematosus (SLE)). Orelabrutinib is a small-molecule Bruton's tyrosine kinase (BTK; Bruton's agammaglobulinemia tyrosine kinase) inhibitor with potential antitumor activity. After administration, orelabrutinib binds to BTK and inhibits its activity. This prevents both activation of the B-cell antigen receptor (BCR) signaling pathway and activation of BTK-mediated downstream survival pathways, thereby inhibiting the growth of BTK-overexpressing malignant B cells. BTK is a member of the Src-associated BTK/Tec family of cytoplasmic tyrosine kinases, which is overexpressed or mutated in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signal transduction, proliferation, and survival.
Orelabrutinib (ICP-022) is a potent, orally active, irreversible BTK inhibitor (IC50 = 1.6 nM). It shows high selectivity and has potential antineoplastic activity. It is currently being investigated in clinical studies for B-cell malignancies. |
| Molecular Formula |
C26H25N3O3
|
|---|---|
| Molecular Weight |
427.4950
|
| Exact Mass |
427.19
|
| Elemental Analysis |
C, 73.05; H, 5.89; N, 9.83; O, 11.23
|
| CAS # |
1655504-04-3
|
| Related CAS # |
1655504-04-3
|
| PubChem CID |
91667513
|
| Appearance |
White to off-white solid powder
|
| LogP |
3.6
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
32
|
| Complexity |
647
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
MZPVEMOYADUARK-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C26H25N3O3/c1-2-24(30)29-16-14-18(15-17-29)23-13-12-22(26(27)31)25(28-23)19-8-10-21(11-9-19)32-20-6-4-3-5-7-20/h2-13,18H,1,14-17H2,(H2,27,31)
|
| Chemical Name |
2-(4-phenoxyphenyl)-6-(1-prop-2-enoylpiperidin-4-yl)pyridine-3-carboxamide
|
| Synonyms |
ICP022; Orelabrutinib; ICP-022; Orelabrutinib [INN]; Orelabrutinib [USAN]; WJA5UO9E10; 6-[1-(1-Oxo-2-propen-1-yl)-4-piperidinyl]-2-(4-phenoxyphenyl)-3-pyridinecarboxamide; ICP 022
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO: 86~100 mg/mL (201.2~233.9 mM)
Ethanol: ~10 mg/mL (~23.4 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.85 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 25.0 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: ≥ 2.5 mg/mL (5.85 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 25.0 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.85 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 | 2.3392 mL | 11.6959 mL | 23.3918 mL | |
| 5 mM | 0.4678 mL | 2.3392 mL | 4.6784 mL | |
| 10 mM | 0.2339 mL | 1.1696 mL | 2.3392 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05036577 | Active Recruiting |
Drug: Orelabrutinib Drug: Rituximab |
Primary Central Nervous System Lymphoma |
Huashan Hospital | October 10, 2021 | Phase 1 |
| NCT04711148 | Active Recruiting |
Other: placebo Drug: orelabrutinib |
Relapsing Remitting Multiple Sclerosis |
Beijing InnoCare Pharma Tech Co., Ltd. |
March 1, 2021 | Phase 2 |
| NCT06115824 | Active Recruiting |
Drug: Orelabrutinib | Primary Central Nervous System Lymphoma |
Huashan Hospital | August 10, 2023 | |
| NCT04304040 | Active Recruiting |
Drug: Orelabrutinib Drug: Recombinant humanized monoclonal antibody MIL62 injection |
B-cell Lymphoma Recurrent B-cell Lymphoma Refractory |
Beijing InnoCare Pharma Tech Co., Ltd. |
July 28, 2020 | Phase 1 Phase 2 |
| NCT04014205 | Active Recruiting |
Drug: Orelabrutinib (ICP-022) |
Part 1：r/r B-cell Malignancies Part 2：B-cell Malignancies |
Beijing InnoCare Pharma Tech Co., Ltd. |
November 18, 2019 | Phase 1 Phase 2 |
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