20S proteasome β5 (IC50 = 3.4 nM); 20S proteasome β1 (IC50 = 31 nM); 20S proteasome β2 (IC50 = 3500 nM)

Ixazomib citrate (MLN9708; 0.20-3.20 μM) 以时间和剂量依赖性方式有效抑制两种细胞系的生长。 ixazomib 在 MG-63 和 Saos-2 细胞中诱导细胞周期停滞。 Ixazomib 需要激活 caspase8 和 caspase9 才能主要通过 caspase 途径诱导细胞凋亡。 ixazomib 治疗可提高促凋亡蛋白水平并降低控制 MOMP 的抗凋亡蛋白水平。 ixazomib 治疗导致线粒体释放 Cytc、Smac 和 OMI，并降低 XIAP 蛋白水平。 Ixazomib 降低 MMP2/9 的表达和分泌水平，并抑制 MG-63 和 Saos-2 细胞的侵袭能力[1]。 Ixazomib citrate (MLN9708; 12 nM) 对 TL 和 CL 蛋白酶体的活性具有抑制作用。 Ixazomib 处理 H929 和 MM.1S MM 细胞会导致聚 (ADP) 核糖聚合酶 (PARP) 蛋白水解裂解显着增加，这是细胞凋亡过程中的标志性事件。上游 PARP 激活剂 caspase-3 被 isxazomib 裂解。 Ixazomib 增加 CHOP/GADD153 和 Bip 蛋白的水平以及 eIf2-α 激酶活性。 Ixazomib 靶向 NF-κB，在体外抑制毛细管形成，并阻断 BMSC 诱导的 MM 细胞增殖 [2]。

Ixazomib citrate (MLN9708；11 mg/kg) 通过显着阻止 MM 肿瘤的生长来提高人浆细胞瘤 MM.1S 异种移植小鼠模型的存活率。使用伊沙佐米治疗的小鼠血液化学特征中的血红蛋白、胆红素和肌酐水平均正常。 ixazomib 显着增加异种移植模型中克隆的 caspase-3 阳性细胞数[2]。

MTT 测定用于确定细胞活力。经胰蛋白酶消化的细胞以每孔 5000 个接种于 96 孔板中。将 Ixazomib 或 DMSO 添加到基础培养基中，并按规定的时间和剂量给予细胞。相对于单独给予媒介物的对照细胞来评估细胞的活力。

Ixazomib is dissolved at a concentration of 2 mg/mL in 5% 2-hydroxypropyl-β-cyclodextrin. The test makes use of a human plasmacytoma xenograft tumor model. After receiving a subcutaneous inoculation of 5.0×106 MM.1S cells in 100 µL serum-free RPMI-1640 medium, 21 CB-17 SCID mice are randomly assigned to treatment groups once their tumors have grown to a size of 250–300 mm3. For three weeks, mice are given vehicle, bortezomib (1 mg/kg; i.v.) or ixazomib (11 mg/kg; i.v.) twice a week. When a tumor grows to be 2 cm3, the animal is put to death.

[1]. A New Perspective for Osteosarcoma Therapy: Proteasome Inhibition by MLN9708/2238 Successfully Induces Apoptosis and Cell Cycle Arrest and Attenuates the Invasion Ability of Osteosarcoma Cells in Vitro. Cell Physiol Biochem. 2017 Jan 27;41(2

[2]. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res. 2011 Aug 15;17(16):5311-21.

[3]. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010 Mar 1;70(5):1970-80.

Ixazomib citrate is a glycine derivative that is the amide obtained by formal condensation of the carboxy group of N-(2,5-dichlorobenzoyl)glycine with the amino group of 2,2'-{2-[(1R)-1-amino-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid. A prodrug for ixazomib that is used in combination therapy for treatment of multiple myeloma. It has a role as a prodrug, a proteasome inhibitor, an orphan drug, an antineoplastic agent and an apoptosis inducer. It is a glycine derivative, a member of benzamides, a dichlorobenzene, an oxo dicarboxylic acid and a 1,3,2-dioxaborolane. It is functionally related to an ixazomib.
Ixazomib Citrate is the citrate salt form of ixazomib, an orally bioavailable second generation proteasome inhibitor (PI) with potential antineoplastic activity. Ixazomib inhibits the activity of the proteasome, blocking the targeted proteolysis normally performed by the proteasome, which results in an accumulation of unwanted or misfolded proteins; disruption of various cell signaling pathways may follow, resulting in the induction of apoptosis. Compared to first generation PIs, second generation PIs may have an improved pharmacokinetic profile with increased potency and less toxicity. Proteasomes are large protease complexes that degrade unneeded or damaged proteins that have been ubiquinated.
See also: Ixazomib (has active moiety).

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Drug Indication
Ninlaro in combination with lenalidomide and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
Treatment of systemic light chain amyloidosis

C₂₀H₂₃BCL₂N₂O₉

517.12

516.087

C, 46.45; H, 4.48; B, 2.09; Cl, 13.71; N, 5.42; O, 27.85

1239908-20-3

Ixazomib;1072833-77-2

56844015

White to off-white solid powder

1.5±0.1 g/cm3

1.580

3.378

175.31

4

9

11

34

797

1

ClC1C([H])=C([H])C(=C([H])C=1C(N([H])C([H])([H])C(N([H])[C@]([H])(B1OC(C(C([H])([H])C(=O)O[H])(C([H])([H])C(=O)O[H])O1)=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)=O)Cl

MBOMYENWWXQSNW-AWEZNQCLSA-N

InChI=1S/C20H23BCl2N2O9/c1-10(2)5-14(21-33-19(32)20(34-21,7-16(27)28)8-17(29)30)25-15(26)9-24-18(31)12-6-11(22)3-4-13(12)23/h3-4,6,10,14H,5,7-9H2,1-2H3,(H,24,31)(H,25,26)(H,27,28)(H,29,30)/t14-/m0/s1

2-[4-(carboxymethyl)-2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-1,3,2-dioxaborolan-4-yl]acetic acid

Ninlaro; MLN9708; MLN 9708; MLN-9708; ixazomib citrate; MMLN 2238-prodrug; MMLN-2238-prodrug; MMLN2238-prodrug; Ixazomib-prodrug

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: 100~250 mg/mL (193.4~483.5 mM)
Ethanol: ~100 mg/mL (~193.4 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.02 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 (4.02 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 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 (4.02 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。