| 规格 | 价格 | 库存 | 数量 |
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| 10 mM * 1 mL in DMSO |
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| 靶点 |
Cereblon E3 ligase
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| 体外研究 (In Vitro) |
体外活性：C-122 是一种治疗 DLBCL 的新型药物，具有抗肿瘤和免疫调节活性。在 DLBCL 细胞系中，它结合 CRBN 并诱导 Aiolos 和 Ikaros 的降解或短发夹 RNA 介导的敲低，这与干扰素 (IFN) 刺激的基因转录增加相关，与 IFN-α、-β 和 -γ 的产生无关和/或分泌并导致活化 B 细胞 (ABC) 和生发中心 B 细胞 DLBCL 细胞系凋亡。 CRBN 是 CC-122 的分子靶标，CC-122 与 CRBN 结合将 Aiolos/Ikaros 招募到 CRL4CRBN，并且 E3 连接酶活性对于 Aiolos 和 Ikaros 泛素化以及 CC-122 诱导的蛋白酶体降解是必需的。 CC-122 诱导 IFN 调节蛋白，其对 IFN 通路的介导作用独立于自分泌 I 型和 II 型 IFN 分泌和信号转导。激酶测定：CC-122 是一种新型 DLBCL 药物，具有抗肿瘤和免疫调节活性。CC-122 结合 CRBN 并降解 Aiolos 和 Ikaros，从而模拟 DLBCL 中的 IFN 信号传导和细胞凋亡。体外：CC122 抑制 ABC 和 GCB DLBCL 的增殖并诱导细胞凋亡。在 DLBCL 细胞系中，CC122 诱导的 Aiolos 和 Ikaros 降解或短发夹 RNA 介导的敲低与干扰素 (IFN) 刺激基因的转录增加相关，与 IFN-α、-β 和 -γ 的产生和/或分泌无关，并且导致活化 B 细胞 (ABC) 和生发中心 B 细胞 DLBCL 凋亡。细胞测定：弥漫性大 B 细胞淋巴瘤在含有 10-20% 胎牛血清、1% 青霉素/链霉素和 1 mM 丙酮酸钠的 RPMI-1640 中培养。每孔 2×104 个细胞接种于含有 DMSO 或不同浓度 CC-122 的培养基中。将细胞在 37 摄氏度下培养 5 天，然后将氚化胸苷添加到细胞培养物中，持续最后 6 小时。随后将细胞收获到过滤板上。板干燥后，将闪烁液添加到板中并在 Top-count 读数器上读取。
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| 体内研究 (In Vivo) |
CC-122 可减少由 ABC- 和 GCB-DLBCL 细胞系建立的异种移植模型中的肿瘤生长，并刺激原代 T 细胞中 IL-2 的产生。此外，在单臂 CC-122 临床试验中，暴露于 CC-122 使每位患者的 Aiolos 和 Ikaros 表达水平降低了 25% 至 50%，证明了这 2 种蛋白质作为 CC-122 药效学标志物的效用
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| 细胞实验 |
CC-122抑制ABC和GCB DLBCL细胞增殖并诱导细胞凋亡[1]
为了探讨CC-122在DLBCL细胞株中的抗增殖活性，在CC-122作用5天后，对一组DLBCL细胞株进行胸苷掺入试验。4个ABC-DLBCL细胞系（TMD8、U2932、Riva和OCI-LY10）和5个GCB-DLBCL细胞系（Karpas 422、WSU-DLCL2、SUDHL-4、OCI-LY19和Pfeiffer）与0.01 ~ 10000 nM CC-122暴露5天，细胞增殖明显降低（图1A）。ABC细胞株比GCB细胞株更敏感(ABC 50%抑制浓度范围为8 nM ~ 6 μM；GCB 50%抑制浓度范围，1 μM ~ >10 μM)。 CC-122促进CRBN-Ikaros相互作用及随后Aiolos和Ikaros的蛋白酶体降解[1] 最近研究表明，CRBN的沙利度胺结合域包含一个疏水性口袋，其中3个色氨酸残基控制着沙利度胺、来那度胺和波马度胺与谷氨酰胺的结合由于CC-122的化学结构中含有一个戊二胺环，我们探索CC-122是否与CRBN结合。如图2A所示，来自U266多发性骨髓瘤细胞提取物的CRBN与连接到固定化沙利度胺类似物（DMSO控制通道）的FG亲和珠相互作用。此外，随着游离CC-122浓度的增加，该复合物的培养导致CRBN从沙利度胺类似物固定的微球中移位，这与CC-122与沙利度胺竞争结合CRBN一致。此外，对纯化的CRBN C端片段（氨基酸321-440）的荧光猝灭研究证实了CC-122与CRBN的直接结合（补充图1）。 |
| 动物实验 |
On the first day of these studies, the female SCID mice (CB17/Icr-Prkdcscid, Charles River) were 8 weeks old and weighed between 15.0 and 23.2 g. Each SCID mouse received a subcutaneous injection of 5x106 OCI-LY10 cells (0.2 ml cell suspension) in the right flank. In order to track growth, tumors were classified in two dimensions as their mean volume got closer to 100–150 mm3. Mice were divided into treatment groups (n=10) after tumor cell implantation, either twenty-one days (OCI-LY10) or fourteen days (WSU-DLCL2). Throughout the study, tumors were called in twice a week.In 0.5% carboxymethyl cellulose:0.25% Tween-80 in de-ionized water, apadomide (CC122) was suspended. For twenty-eight days (qd x28), avadomide (CC122) and the vehicle were each given by oral gavage (p.o.) once daily. [1]
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| 药代性质 (ADME/PK) |
Pharmacokinetics, pharmacodynamics, and biomarkers[1]
At all dose levels, the avadomide plasma concentration versus time profiles were characterized by a rapid absorption phase and similar median time to maximum concentration (Fig. 1). After attainment of maximum observed concentration in plasma, avadomide appeared to decrease in a monophasic manner at all dose levels. By visual inspection of mean plasma concentrations versus time profiles, avadomide plasma exposures increased in a dose-dependent manner across the 0.5- to 3.5-mg dose range. All 7 dose levels showed mild-to-moderate accumulation of avadomide plasma exposure after multiple doses. Supplementary Table S1 summarizes avadomide plasma pharmacokinetic parameters by day and dose level. In general, as assessed from the geometric coefficient of variation percentage, interpatient variability was noted for both avadomide area under the concentration–time curve and maximum observed concentration in plasma. The mean total recovery of avadomide in urine within 24 hours ranged from 18% to 35% across the 0.5- to 3.5-mg dose range. The mean avadomide renal clearance ranged from 0.53 to 1.31 L/h across the 0.5- to 3.5-mg dose range. The t1/2 ranged from 7.68 to 27.91 hours. |
| 毒性/毒理 (Toxicokinetics/TK) |
Most patients (85%) had ≥1 TEAE that was suspected by the investigators of being related to avadomide. Across all cohorts, the most common TEAEs (≥15%) were fatigue (44%), neutropenia (29%), and diarrhea (15%). Avadomide-related grade ≥3 TEAEs occurred in 14 patients (41%). The most common grade ≥3 TEAEs were neutropenia (2 patients in the 1.0-mg cohort; 1 patient each in the 1.5-, 2.0-, 2.5-, and 3.5-mg cohorts; and 3 patients in the 3.0-mg cohort) and pneumonia (2 patients in the 3.0-mg cohort). Table 2 summarizes the TEAEs in the treated population. One death occurred within 28 days of the last dose of avadomide; 1 patient with pancreatic carcinoma in the 3.5-mg cohort died due to disease progression.
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| 参考文献 | |
| 其他信息 |
Avadomide is under investigation in clinical trial NCT02031419 (Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma).
Avadomide is a novel, small molecule cereblon-modulating agent with potential antineoplastic, antiangiogenic and immunomodulatory activities. Upon oral administration, avadomide binds to and modulates cereblon to promote recruitment of the hematopoietic transcription factors Aiolos and Ikaros to the Cullin-4 RING E3 ubiquitin ligase complex. This binding results in the ubiquitination and rapid proteasomal degradation of Aiolos and Ikaros and the derepression of interferon (IFN)-stimulated genes, including DDX58 and IRF7, leading to apoptosis of certain tumor cells. Additionally, Aiolos degredation leads to derepression of the IL2 gene, thereby enhancing interleukin-2 production, costimulation of T-lymphocytes and IL-2-induced T-cell proliferation. Avadomide may also promote the activation of natural killer (NK) cells, potentially enhancing tumor cell killing. Aiolos and Ikaros are transcriptional repressors known to play an important role in normal B- and T-cell function. Drug Indication Treatment of mature B-cell neoplasms |
| 分子式 |
C14H14N4O3
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|---|---|
| 分子量 |
286.29
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| 精确质量 |
286.107
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| 元素分析 |
C, 58.74; H, 4.93; N, 19.57; O, 16.77
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| CAS号 |
1015474-32-4
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| 相关CAS号 |
(S)-Avadomide-d1;1620055-10-8
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| PubChem CID |
24967599
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| 外观&性状 |
White to gray solid powder
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| LogP |
1.174
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| tPSA |
107.08
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
5
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| 可旋转键数目(RBC) |
1
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| 重原子数目 |
21
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| 分子复杂度/Complexity |
530
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| 定义原子立体中心数目 |
0
|
| SMILES |
O=C1C([H])(C([H])([H])C([H])([H])C(N1[H])=O)N1C(C2=C(C([H])=C([H])C([H])=C2N=C1C([H])([H])[H])N([H])[H])=O
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| InChi Key |
RSNPAKAFCAAMBH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H14N4O3/c1-7-16-9-4-2-3-8(15)12(9)14(21)18(7)10-5-6-11(19)17-13(10)20/h2-4,10H,5-6,15H2,1H3,(H,17,19,20)
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| 化学名 |
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
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| 别名 |
Avadomide; CC 122; CC-122; 1015474-32-4; 3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; Avadomide [USAN]; Avadomide(CC-122); CC 122; CC122
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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 |
| 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) |
DMSO : 33.33~57 mg/mL ( 116.42~199.09 mM )
Ethanol : ~1 mg/mL |
|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (8.73 mM) (饱和度未知) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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。 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。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4930 mL | 17.4648 mL | 34.9296 mL | |
| 5 mM | 0.6986 mL | 3.4930 mL | 6.9859 mL | |
| 10 mM | 0.3493 mL | 1.7465 mL | 3.4930 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) 。
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03283202 | Completed | Drug: Avadomide (CC-122) Drug: Rituximab |
Diffuse B-Cell Lymphoma | Celgene | October 4, 2017 | Phase 1 |
| NCT03834623 | Completed | Drug: CC-122 Drug: Nivolumab |
Melanoma | H. Lee Moffitt Cancer Center Research Institute |
May 14, 2019 | Phase 2 |
| NCT03310619 | Completed | Biological: JCAR017 Drug: Durvalumab Drug: CC-122 |
Lymphoma, Non-Hodgkin Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular |
Celgene | November 28, 2017 | Phase 1 Phase 2 |
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BC-1215
Smurf1-IN-A01
Eragidomide (CC-90009)
VL285
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