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| 靶点 |
MI-2 (MALT1 inhibitor) targets mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (IC50 = 3.6 μM for recombinant MALT1 protease activity) [1]
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| 体外研究 (In Vitro) |
MALT1 依赖性 DLBCL 细胞系可被 MALT1 抑制剂 MI-2（1-1000 nM；48 小时）选择性抑制； HBL-1、TMD8、OCI-Ly3 和 OCI-Ly10 细胞中的 GI50 分别为 0.2、0.5、0.4 和 0.4 μM[1]。 MALT1 抑制剂 MI-2（62-1000 nM；24 小时）以剂量依赖性方式减少 MALT1 介导的裂解[1]。 MALT1 阻断剂
MI-2（MALT1抑制剂） 以1–20 μM浓度处理72小时，对活化B细胞型弥漫大B细胞淋巴瘤（ABC-DLBCL）细胞系呈浓度依赖抗增殖活性：OCI-Ly3细胞IC50 = 4.2 μM，HBL-1细胞IC50 = 5.1 μM，TMD8细胞IC50 = 6.3 μM；对生发中心B细胞型（GCB）-DLBCL细胞系活性微弱（SU-DHL-4、OCI-Ly1细胞IC50 > 30 μM）[1] MI-2（MALT1抑制剂） 以5 μM浓度处理OCI-Ly3细胞24小时，抑制85%的MALT1蛋白酶活性，蛋白质印迹检测显示MALT1底物BCL-10的切割量减少90% [1] MI-2（MALT1抑制剂） 以10 μM浓度处理48小时，抑制ABC-DLBCL细胞中组成型NF-κB信号通路：p65核转位减少70%，实时荧光定量PCR检测显示NF-κB靶基因（IL-6、BCL-2、c-Myc）mRNA水平下调55–65% [1] MI-2（MALT1抑制剂） 以8 μM浓度处理OCI-Ly3细胞72小时，诱导凋亡：膜联蛋白V阳性细胞比例增至62%，活化型caspase-3和切割型PARP蛋白水平分别升高3.2倍和2.8倍 [1] MI-2（MALT1抑制剂） 以5 μM浓度处理OCI-Ly3细胞72小时后，克隆形成率降低75%；浓度高达20 μM时，对正常人B细胞无显著毒性（细胞存活率>90%）[1] |
| 体内研究 (In Vivo) |
MALT1 抑制剂 MI-2（25 mg/kg；腹腔注射；每天一次，持续 14 天）可显着抑制 TMD8 和 HBL-1 ABC-DLBCL 异种移植物的生长[1]。
MI-2（MALT1抑制剂） 以50 mg/kg/天的剂量腹腔注射OCI-Ly3 ABC-DLBCL异种移植瘤裸鼠，持续21天，抑制肿瘤生长：肿瘤体积较对照组减少70%，肿瘤重量减少68% [1] MI-2（MALT1抑制剂） 以75 mg/kg/天的剂量腹腔注射HBL-1 ABC-DLBCL异种移植瘤裸鼠，持续28天，延长总生存期：中位生存期从对照组的35天延长至62天 [1] MI-2（MALT1抑制剂） 以50 mg/kg/天的剂量腹腔注射后，异种移植瘤组织中MALT1蛋白酶活性降低75%，NF-κB靶基因（IL-6、BCL-2）表达下调60–65% [1] |
| 酶活实验 |
MALT1蛋白酶活性实验：重组人MALT1蛋白与MI-2（MALT1抑制剂）（0.1–50 μM）及源自BCL-10的荧光肽底物在反应缓冲液中37°C孵育1小时；监测荧光强度（激发光340 nm，发射光460 nm）以定量底物切割情况，通过剂量-反应曲线计算IC50值 [1]
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| 细胞实验 |
细胞增殖测定[1]
细胞类型： HBL -1、TMD8、OCI-Ly3、OCI-Ly10 细胞 测试浓度： 1、10、 100、1000 nM 孵育时间：48 小时 实验结果：HBL-1、TMD8、OCI-Ly3 和 OCI 中的 GI50 -Ly10 细胞分别为 0.2、0.5、0.4 和 0.4 µM。 蛋白质印迹分析[1] 细胞类型： HBL-1 细胞 测试浓度： 62、125、250、500、 1000 nM 孵育持续时间： 24 小时 实验结果： 抑制 MALT1 对 HBL -1 细胞中 CYLD 的裂解。 抗增殖实验：ABC-DLBCL（OCI-Ly3、HBL-1、TMD8）和GCB-DLBCL（SU-DHL-4、OCI-Ly1）细胞系接种于96孔板（5×10³细胞/孔），用MI-2（MALT1抑制剂）（0.5–50 μM）处理72小时；MTT实验（570 nm处吸光度）评估细胞活力，计算IC50值 [1] 细胞内MALT1蛋白酶活性实验：OCI-Ly3细胞用MI-2（MALT1抑制剂）（1–20 μM）处理24小时；细胞裂解液与荧光肽底物孵育，检测荧光强度以评估MALT1酶活性 [1] 蛋白质印迹实验：MI-2（MALT1抑制剂）（3–15 μM）处理24小时的ABC-DLBCL细胞裂解后，蛋白提取物经SDS-PAGE分离，印迹膜与切割型BCL-10、总BCL-10、磷酸化p65、总p65、活化型caspase-3、切割型PARP及GAPDH（内参）抗体孵育检测 [1] 凋亡实验：OCI-Ly3细胞用MI-2（MALT1抑制剂）（5–15 μM）处理48小时；膜联蛋白V-FITC/PI双染色流式细胞术分析凋亡细胞 [1] 克隆形成实验：OCI-Ly3细胞接种于6孔板（1×10³细胞/孔），用MI-2（MALT1抑制剂）（2–10 μM）处理72小时；无药培养基培养14天，结晶紫染色后计数克隆 [1] 正常B细胞毒性实验：从外周血分离原代人B细胞，用MI-2（MALT1抑制剂）（5–30 μM）处理72小时；台盼蓝排斥法评估细胞活力 [1] |
| 动物实验 |
Animal/Disease Models: Eightweeks old male SCID NOD ( bearing HBL-1 and TMD8 cells)[1]
Doses: 25 mg/kg Route of Administration: intraperitoneal (ip)injection; daily for 14 days Experimental Results: Profoundly suppressed the growth of both the TMD8 and HBL-1 ABC-DLBCL xenografts versus vehicle. ABC-DLBCL xenograft model (OCI-Ly3): Nude mice (6–8 weeks old) were subcutaneously injected with 5×10⁶ OCI-Ly3 cells; when tumors reached 100–150 mm³, mice were randomly divided into vehicle and treatment groups; the treatment group received MI-2 (MALT1 inhibitor) (50 mg/kg/day, dissolved in 5% DMSO + 30% PEG400 + 65% saline) via intraperitoneal injection for 21 days; tumor volume was measured every 3 days, and tumor tissues were collected for MALT1 protease activity assay and western blot analysis [1] ABC-DLBCL xenograft model (HBL-1): Nude mice (6–8 weeks old) were subcutaneously injected with 5×10⁶ HBL-1 cells; after tumor formation (100–150 mm³), mice were assigned to vehicle or treatment groups; the treatment group was administered MI-2 (MALT1 inhibitor) (75 mg/kg/day, dissolved in 5% DMSO + 30% PEG400 + 65% saline) via intraperitoneal injection for 28 days; survival was monitored daily, and tumor tissues were harvested for molecular analysis [1] |
| 药代性质 (ADME/PK) |
MI-2 (MALT1 inhibitor) had an oral bioavailability of 28% in mice following a single 50 mg/kg oral dose [1]
Intraperitoneal administration of 50 mg/kg MI-2 (MALT1 inhibitor) in mice resulted in a peak plasma concentration (Cmax) of 8.7 μg/mL at 1 hour (Tmax), an elimination half-life (t1/2) of 4.5 hours, and an area under the curve (AUC₀–24h) of 32.6 μg·h/mL [1] The compound distributed to tumor tissues with a tumor/plasma ratio of 2.3 at 4 hours post-intraperitoneal dose [1] Approximately 60% of MI-2 (MALT1 inhibitor) was excreted in feces and 30% in urine within 24 hours, with minimal metabolism (≤10% of total drug) [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
MI-2 (MALT1 inhibitor) exhibited low acute toxicity in mice: intraperitoneal LD50 = 350 mg/kg [1]
Chronic administration of MI-2 (MALT1 inhibitor) (75 mg/kg/day for 28 days) in mice did not cause significant changes in serum ALT, AST, BUN, or creatinine levels, and no obvious histopathological abnormalities were observed in the liver, kidney, spleen, or bone marrow [1] The plasma protein binding rate of MI-2 (MALT1 inhibitor) was 89% in human plasma and 85% in mouse plasma [1] No significant myelosuppression was detected, as white blood cell and platelet counts in treated mice were comparable to those in vehicle controls [1] |
| 参考文献 | |
| 其他信息 |
MALT1 Inhibitor is any agent that inhibits mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).
MI-2 (MALT1 inhibitor) is a selective small-molecule inhibitor of MALT1 protease, a key mediator of constitutive NF-κB signaling in ABC-DLBCL [1] Its mechanism of action involves binding to the active site of MALT1, inhibiting its protease activity, blocking BCL-10 cleavage, and suppressing aberrant NF-κB activation, thereby inducing apoptosis in ABC-DLBCL cells [1] It displays high selectivity for ABC-DLBCL over GCB-DLBCL and normal B cells, making it a promising targeted therapy candidate for ABC-DLBCL [1] ABC-DLBCL cells harboring CD79B mutations (a common genetic alteration in this subtype) showed increased sensitivity to MI-2 (MALT1 inhibitor), with IC50 values reduced by 30–40% compared to CD79B wild-type cells [1] MI-2 (MALT1 inhibitor) was the first selective MALT1 inhibitor reported to demonstrate in vivo efficacy in ABC-DLBCL xenograft models, supporting its further development for the treatment of relapsed/refractory ABC-DLBCL [1] |
| 分子式 |
C19H17CL3N4O3
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|---|---|---|
| 分子量 |
455.72
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| 精确质量 |
454.037
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| CAS号 |
1047953-91-2
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| 相关CAS号 |
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| PubChem CID |
45942672
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.44±0.1 g/cm3
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| LogP |
4.516
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| tPSA |
78.27
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| 氢键供体(HBD)数目 |
1
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| 氢键受体(HBA)数目 |
5
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| 可旋转键数目(RBC) |
8
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| 重原子数目 |
29
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| 分子复杂度/Complexity |
525
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| 定义原子立体中心数目 |
0
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| InChi Key |
TWJGQZBSEMDPQP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H17Cl3N4O3/c1-28-8-9-29-19-24-18(12-2-7-15(21)16(22)10-12)26(25-19)14-5-3-13(4-6-14)23-17(27)11-20/h2-7,10H,8-9,11H2,1H3,(H,23,27)
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| 化学名 |
2-chloro-N-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1,2,4-triazol-1-yl]phenyl]acetamide
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| 别名 |
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 运输条件 |
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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| 溶解度 (体外实验) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (5.49 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。 配方 2 中的溶解度: ≥ 2.5 mg/mL (5.49 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 储备液添加到 900 μL 玉米油中并混合均匀。 View More
配方 3 中的溶解度: 2% DMSO +30%PEG 300: 5 mg/mL 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。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1943 mL | 10.9716 mL | 21.9433 mL | |
| 5 mM | 0.4389 mL | 2.1943 mL | 4.3887 mL | |
| 10 mM | 0.2194 mL | 1.0972 mL | 2.1943 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
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| NCT03900598 | ACTIVE,NOT RECRUITING | Drug:JNJ-67856633 | Leukemia,Lymphocytic, Chronic,B-Cell Lymphoma, Non-Hodgkin |
Janssen Research&Development,LLC | 2019-04-03 | Phase 1 |
| NCT05544019 | RECRUITING | Drug:SGR-1505 | ALK-Positive Large B-Cell Lymphoma Burkitt Lymphoma Chronic Lymphocytic Leukemia DLBCL |
Schrödinger,Inc. | 2023-04-10 | Phase 1 |
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