Orelabrutinib   中文名称: 奥布替尼

BTK/Bruton's Tyrosine Kinase

Orelabrutinib 的 IC50 值为 1.6 nM，有效抑制 BTK 酶活性。在 1 μM 平行 KINOMEscan 检测中，奥布替尼仅以 BTK 为目标，针对 456 种激酶具有 > 90% 的抑制率，而依鲁替尼可抑制许多其他激酶，如 EGFR、TEC 和 BMX，这表明奥布替尼具有卓越的激酶选择性。 [2]

奥布替尼在临床前 PK/PD 研究中表现出良好的 PK 特性，理想的 T1/2 约为 1.5-4 小时，口服生物利用度约为 20-80%，并且 BTK 靶点占用时间较长。在大鼠和狗的 GLP 毒理学研究中，更高的选择性导致更高的安全性和更宽的安全窗。 [2]

Ibrutinib, orelabrutinib和zanubrutinib都是布鲁顿酪氨酸激酶抑制剂，极大地改善了b细胞恶性肿瘤的治疗。本研究建立并验证了hplc -MS/MS法测定人血浆中orelabrutinib、zanubrutinib、ibrutinib及其活性代谢物二氢二醇ibrutinib的含量。采用Ibrutinib-d5作为内标。用乙腈进行简单的蛋白质沉淀预处理。采用ACQUITY UPLC HSS T3色谱柱(2.1×50 mm, 1.8 μm)分离，运行时间6.5 min，流动相为乙腈-甲酸铵10 mm，甲酸含量为0.1%。采用正离子电喷雾电离法，选择orelabrutinib、zanubrutinib、ibrutinib、dihydrodiol ibrutinib和ibrutinib-d5在m/z 428.1→411.2、472.2→455.2、441.1→304.2、475.2→304.2和446.2→309.2的多重反应监测跃迁。依鲁替尼和二氢二醇依鲁替尼的标准曲线为0.400 ~ 200 ng/mL，奥瑞布替尼为1.00 ~ 500 ng/mL，扎鲁替尼为2.00 ~ 1000 ng/mL，均呈线性。选择性、定量下限、精密度、准确度、基质效应、回收率、稳定性和稀释完整性均符合FDA指南的接受标准。该方法用于定量临床患者血浆中orelabrutinib、zanubrutinib、ibrutinib和dihydrodiol ibrutinib的水平。Molecules . 2023 Jan 26;28(3):1205.

采用新型口服BTK抑制剂Orelabrutinib联合Bcl-2抑制剂venetoclax验证DHL的抗肿瘤作用。使用细胞计数试剂盒-8和Annexin V-FITC/PI检测该联合方案对DHL细胞系和原发性淋巴瘤细胞的相互作用。采用RNA测序、EdU掺入法、线粒体膜电位法和western blotting方法，探讨orelabrutinib加或不加venetoclax对DHL细胞株细胞毒性的分子机制。 结果:本研究中，orelabrutinib联合venetoclax协同诱导DHL细胞死亡，表现为通过线粒体途径抑制细胞增殖，诱导细胞周期阻滞，促进细胞凋亡。奥瑞布替尼治疗改变了DHL细胞的全基因组基因表达。联合用药降低了BTK和Mcl-1的表达，可能会干扰PI3K/AKT信号和p38/MAPK信号的活性和串扰。此外，orelabrutinib和venetoclax联合使用在原发性b淋巴瘤细胞中显示细胞毒性活性。 结论:总之，这些发现揭示了一种针对BCR信号和Bcl-2家族的治疗预后不良的DHL患者的新疗法。J Cancer Res Clin Oncol . 2023 Aug;149(9):5513-5529.

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]

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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]

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]

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]

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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.

[1]. Safety, Tolerability and Efficacy of Orelabrutinib, Once a Day, to Treat Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia. Blood (2019) 134 (Supplement_1): 4319.

[2]. BTK Inhibitor ICP-022.

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.

C26H25N3O3

427.4950

427.19

C, 73.05; H, 5.89; N, 9.83; O, 11.23

1655504-04-3

1655504-04-3

91667513

White to off-white solid powder

3.6

85.5

1

4

6

32

647

0

MZPVEMOYADUARK-UHFFFAOYSA-N

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)

2-(4-phenoxyphenyl)-6-(1-prop-2-enoylpiperidin-4-yl)pyridine-3-carboxamide

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 86~100 mg/mL (201.2~233.9 mM)
Ethanol: ~10 mg/mL (~23.4 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.85 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.85 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.85 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。