BTK/Bruton tyrosine kinase
(±)-Zanubrutinib (BGB-3111) targets Bruton's tyrosine kinase (BTK), a core component of the B-cell receptor (BCR) signaling pathway; it exhibits nanomolar-level inhibitory activity against BTK, [1]

(±)-Zanubrutinib ((±)-BGB-3111) 在生化和细胞测定中均表现出纳摩尔级 Btk 抑制活性。 (±)-Zanubrutinib 抑制 BCR 聚集触发的 Btk 自磷酸化，阻断下游 PLC-γ2 信号传导，并有效抑制多种 MCL 和 DLBCL 细胞系的细胞增殖。当涉及包括 ITK 在内的一组激酶时，与 PCI-32765 相比，(±)-Zanubrutinib 表现出的脱靶活性要有限得多[1]。

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1. 在生化和细胞实验中，(±)-Zanubrutinib对BTK表现出纳摩尔级的抑制效力，相较于伊布替尼，其对BTK的抑制具有高度选择性，对ITK等其他激酶的脱靶活性显著降低[1]
2. 在多种套细胞淋巴瘤（MCL）和弥漫大B细胞淋巴瘤（DLBCL）细胞系中，(±)-Zanubrutinib可抑制由BCR聚集触发的BTK自磷酸化，阻断下游PLC-γ2信号传导，并强效抑制肿瘤细胞增殖[1]
3. 伊布替尼会通过抑制ITK激酶活性拮抗利妥昔单抗诱导的抗体依赖性细胞介导的细胞毒性（ADCC），而(±)-Zanubrutinib对ITK的抑制作用极弱，其抑制利妥昔单抗诱导的ADCC的能力比伊布替尼弱至少10倍，具体表现为对利妥昔单抗诱导的NK细胞IFN-γ分泌及对MCL细胞的体外细胞毒性的抑制作用显著降低[1]

(±)-Zanubrutinib 对注射到小鼠尾静脉并皮下或全身移植的 REC-1 MCL 异种移植物产生剂量依赖性抗肿瘤作用。在放置在皮下的异种移植物中。一项最初的 14 天大鼠毒性研究表明，(±)-Zanubrutinib 具有高度良好的耐受性，剂量高达 250 mg/kg/天也不会达到最大耐受剂量 (MTD)[1]。

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1. 在小鼠BTK占据实验中，(±)-Zanubrutinib以剂量依赖性方式占据PBMC和脾脏等靶器官中的BTK，且在这些器官中的效力比伊布替尼高约3倍[1]
2. (±)-Zanubrutinib对REC-1 MCL异种移植小鼠（皮下和尾静脉注射的系统模型）均表现出剂量依赖性的抗肿瘤效果：在皮下移植模型中，(±)-Zanubrutinib以2.5 mg/kg每日两次（BID）给药，与伊布替尼50 mg/kg每日一次（QD，临床相关剂量）的抗肿瘤活性相当[1]
3. 在REC-1 MCL系统移植模型中，(±)-Zanubrutinib25 mg/kg BID给药组小鼠的中位生存期显著长于伊布替尼50 mg/kg QD及BID给药组[1]
4. 在ABC亚型DLBCL（TMD-8）皮下移植模型中，(±)-Zanubrutinib展现出比伊布替尼更优的抗肿瘤活性[1]

在生化和细胞实验中，BGB-3111显示出纳米级的BTK抑制活性。在一些MCL和DLBCL细胞系中，BGB-3111抑制BCR聚集引发的BTK自磷酸化，阻断下游PLC-γ2信号传导，并有效抑制细胞增殖。与依鲁替尼相比，BGB-3111对一组激酶(包括ITK)显示出更有限的脱靶活性。虽然伊鲁替尼显著抑制利妥昔单抗诱导的NK细胞IFN-γ分泌和对套细胞淋巴瘤细胞的体外细胞毒性，但BGB-3111对利妥昔单抗诱导的ADCC的抑制作用至少弱于伊鲁替尼的10倍，这与其较弱的ITK抑制活性一致。[1]

1. BTK信号抑制实验：培养MCL和DLBCL细胞系，在(±)-Zanubrutinib不同浓度处理下诱导BCR聚集，裂解细胞后通过相关生化方法检测BTK自磷酸化水平及下游PLC-γ2信号通路激活情况，评估药物对BCR-BTK信号通路的抑制作用[1]
2. 细胞增殖实验：将MCL和DLBCL细胞系接种于培养板，加入(±)-Zanubrutinib处理，孵育一段时间后采用合适的细胞活力检测方法评估细胞增殖情况，明确药物的抗增殖效应[1]
3. ADCC抑制实验：将NK细胞与MCL靶细胞和利妥昔单抗共培养，同时加入(±)-Zanubrutinib或伊布替尼处理，检测NK细胞的IFN-γ分泌水平并评估其对MCL细胞的体外细胞毒性，对比两种药物对利妥昔单抗诱导的ADCC的影响[1]

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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1. Mouse BTK occupancy assay: (±)-Zanubrutinib was administered to mice at different doses; at specific time points, PBMC and spleen tissues were collected, and the level of BTK occupancy in these tissues was detected to assess the target engagement of the drug [1]
2. REC-1 MCL subcutaneous xenograft model: REC-1 MCL cells were subcutaneously engrafted into mice; when tumors reached a certain volume, (±)-Zanubrutinib was administered at 2.5 mg/kg BID, and ibrutinib was administered at 50 mg/kg QD as a control; tumor growth was monitored regularly to evaluate the anti-tumor activity of the drug [1]
3. REC-1 MCL systemic xenograft model: REC-1 MCL cells were injected into mice via tail vein to establish a systemic tumor model; (±)-Zanubrutinib was administered at 25 mg/kg BID, and ibrutinib at 50 mg/kg QD/BID as controls; the survival time of mice was recorded to compare the anti-tumor efficacy of different treatments [1]
4. TMD-8 DLBCL subcutaneous xenograft model: TMD-8 DLBCL cells were subcutaneously engrafted into mice; (±)-Zanubrutinib and ibrutinib were administered respectively, and tumor growth was monitored to evaluate the anti-tumor activity of (±)-Zanubrutinib [1]
5. Rat toxicity study: (±)-Zanubrutinib was administered to rats at doses up to 250 mg/kg/day for 14 consecutive days; the general condition of rats was observed, and the maximum tolerated dose (MTD) was evaluated [1]

1. In a 14-day preliminary toxicity study in rats, (±)-Zanubrutinib was well tolerated at doses up to 250 mg/kg/day, and the maximum tolerated dose (MTD) was not reached during the study [1]

[1]. BGB-3111 is a novel and highly selective Bruton's tyrosine kinase (BTK) inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): A.

See also: Zanubrutinib (annotation moved to).

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1. BTK is an essential component of the BCR pathway and a novel therapeutic target for B-cell malignancies; the first-generation irreversible BTK inhibitor ibrutinib has promising clinical activity but can antagonize rituximab-induced ADCC by inhibiting ITK kinase activity, which limits its clinical application [1]
2. (±)-Zanubrutinib is a novel, highly selective second-generation BTK inhibitor, currently under clinical investigation for the treatment of hematological cancers [1]
3. (±)-Zanubrutinib does not affect rituximab-induced ADCC and has better anti-tumor efficacy than ibrutinib in xenograft models, supporting further clinical investigation of this compound as a single agent or in combination with anti-CD20 antibodies for hematological cancers [1]

C27H29N5O3

471.56

471.227

C, 68.77; H, 6.20; N, 14.85; O, 10.18

1633350-06-7

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)

135905454

White to light yellow solid

1.3±0.1 g/cm3

713.4±60.0 °C at 760 mmHg

385.2±32.9 °C

0.0±2.3 mmHg at 25°C

1.680

3.64

103

2

5

6

35

756

0

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

RNOAOAWBMHREKO-UHFFFAOYSA-N

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)

2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

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)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.41 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 20.8 mg/mL澄清DMSO储备液加入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: 2.08 mg/mL (4.41 mM) 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), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 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: ≥ 2.08 mg/mL (4.41 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 20.8 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。