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Purity: ≥98%
Orelabrutinib (ICP-022; ICP022; ICP 022) is an oral bioavailable, new generation and irreversible/covalent Bruton's tyrosine kinase (BTK) inhibitor with the potential to be used for the treatment of cancer such as B-cell lymphomas and autoimmune indications. Orelabrutinib was first approved in China in December 2020 for the treatment of patients who have had at least one prior treatment for mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL). China and the United States are conducting clinical trials for a variety of orelabrutinib indications.
| Targets |
BTK/Bruton's Tyrosine Kinase
|
|---|---|
| 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]
|
| 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]
|
| 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.
|
| 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.
|
| 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] |
| ADME/Pharmacokinetics |
Systemic exposure (both AUC and Cmax) was in a well dose proportional manner, indicating a good linear PK. The mean terminal T1/2 was approximately 4 hours across all cohorts. There was no drug accumulation in plasma after repeated dosing. No significant food effect was observed following co-administration with a standard high-fat, high-calorie meal.[2]
|
| Toxicity/Toxicokinetics |
The most frequent (≥15%) any grade adverse events (AEs) of any cause were well characterized hematological toxicities: thrombocytopenia, neutropenia, and anemia; and respiratory system infections as well as purpura. No case of atrial fibrillation or secondary malignancy was reported. The most frequently (≥10%) reported ≥ Grade 3 AEs of any cause were neutropenia, thrombocytopenia, lung infection. Twenty-five pts experienced at least one serious AE. Of those, 13 were considered related to Orelabrutinib treatment, including platelet count decrease (3 pts), pneumonitis, pyrexia (2 pts each) and herpes zoster etc. (1 pt each). [1]
Orelabrutinib was safe and well tolerated in healthy subjects who received a single dose up to 400 mg or multiple doses up to 100 mg BID or 200 mg QD for 14 days. All treatment-emergent adverse events (TEAEs) reported during the study were mild or moderate in severity and resolved before the end of studies. Petechiae and headache were the most commonly reported treatment related TEAEs. No dose limiting toxicities (DLT) were encountered, and the maximum tolerated dose (MTD) was not reached. No serious TEAEs, TEAEs leading to treatment withdrawal, or serious TEAEs resulting in death were reported during this study. |
| References | |
| Additional Infomation |
Orelabrutinib is under investigation in clinical trial NCT04305197 (A Study of ICP-022 in Patients With Systemic Lupus Erythematosus (SLE)).
Orelabrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK; Bruton agammaglobulinemia tyrosine kinase) with potential antineoplastic activity. Upon administration, orelabrutinib binds to and inhibits the activity of BTK. This prevents both the activation of the B-cell antigen receptor (BCR) signaling pathway and BTK-mediated activation of downstream survival pathways, inhibiting the growth of malignant B-cells that overexpress BTK. BTK, a member of the Src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed or mutated in B-cell malignancies; it plays an important role in the development, activation, signaling, proliferation and survival of B-lymphocytes. |
| Molecular Formula |
C26H25N3O3
|
|---|---|
| Molecular Weight |
427.4950
|
| Exact Mass |
427.19
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| Elemental Analysis |
C, 73.05; H, 5.89; N, 9.83; O, 11.23
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| CAS # |
1655504-04-3
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| 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
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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)
|
| Solubility (In Vitro) |
DMSO: 86~100 mg/mL (201.2~233.9 mM)
Ethanol: ~10 mg/mL (~23.4 mM) |
|---|---|
| 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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