ISA-2011B
目录号 : GC32691
ISA-2011B是一种二酮哌嗪并合的C-1吲哚-3-基取代四氢异喹啉类化合物，可特异性抑制PIP5Kα及相关AKT信号通路。
Cas No.:1395347-24-6
Sample solution is provided at 25 µL, 10mM.
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ISA-2011B, a diketopiperazine fused C-1 indol-3-yl substituted tetra-hydro-isoquinoline, specifically inhibiting the PIP5Kα and the related AKT pathways[1]. ISA-2011B acts as a novel type of anticancer compound that targets PCa cells by targeting AKT/AR-related pathways without toxicity[2].
In vitro, ISA-2011B treatment in primary T cells and Jurkat cells at 25µM for 6h strongly impaired CD3/CD28-mediated induction of PIP5Kα kinase activity and reduced IL-2 mRNA levels, accompanied by cell death[3]. Treatment of C4-2 cells with 50µM ISA-2011B for 48h resulted in a significant down-regulation of cyclin A1, inhibition of cell proliferation and migration, and a decrease in the expression of phosphorylated Ser-473 AKT[4]. Treatment of PC-3 cells with 25µM ISA-2011B for 48 hours resulted in a significant increase in both early and late apoptosis/necrosis[5].
In vivo, ISA-2011B treatment via intraperitoneal injection (40mg/kg; once every other day; i.p.) for 24 days significantly inhibited tumor growth and invasion in the xenograft tumor mouse models[6]. Intraperitoneal injection of ISA-2011B at a dose of 40mg/kg (once every other day) for 15 days suppressed the aggressive growth of AR-V7-overexpressing tumors in xenograft mice, disrupting the PIP5K1α-dependent protein stability of AR-V7[7].
References:
[1] Jin Y, Xue J. Lipid kinases PIP5Ks and PIP4Ks: potential drug targets for breast cancer[J]. Frontiers in Oncology, 2023, 13: 1323897.
[2] Yin M, Wang Y. The role of PIP5K1A in cancer development and progression[J]. Medical Oncology, 2022, 39(10): 151.
[3] Kunkl M, Porciello N, Mastrogiovanni M, et al. ISA-2011B, a phosphatidylinositol 4-phosphate 5-kinase α inhibitor, impairs CD28-dependent costimulatory and pro-inflammatory signals in human T lymphocytes[J]. Frontiers in Immunology, 2017, 8: 502.
[4] Wang T, Sarwar M, Whitchurch J B, et al. PIP5K1α is required for promoting tumor progression in castration-resistant prostate cancer[J]. Frontiers in cell and developmental biology, 2022, 10: 798590.
[5] Semenas J, Wang T, Sajid Syed Khaja A, et al. Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer[J]. Molecular Oncology, 2021, 15(4): 968-986.
[6] Sarwar M, Syed Khaja A S, Aleskandarany M, et al. The role of PIP5K1α/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1α inhibitor[J]. Oncogene, 2019, 38(3): 375-389.
[7] Sarwar M, Semenas J, Miftakhova R, et al. Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells[J]. Oncotarget, 2016, 7(39): 63065.
ISA-2011B是一种二酮哌嗪并合的C-1吲哚-3-基取代四氢异喹啉类化合物，可特异性抑制PIP5Kα及相关AKT信号通路 [1]。ISA-2011B是一种新型抗癌剂，通过靶向AKT/AR相关通路选择性作用于前列腺癌细胞，且不产生毒性作用[2]。
在体外，25µM 的ISA-2011B处理原代T细胞和Jurkat细胞6小时，可显著抑制CD3/CD28介导的PIP5Kα激酶活性升高，降低IL-2 mRNA水平并引发细胞死亡[3]。50µM的ISA-2011B处理C4-2细胞48小时能显著下调细胞周期蛋白A1表达，抑制细胞增殖与迁移，并降低磷酸化Ser-473 AKT水平[4]。25µM的ISA-2011B处理PC-3细胞48小时可显著增加早期与晚期凋亡/坏死率[5]。
在体内，异种移植瘤小鼠模型经腹腔注射ISA-2011B（40mg/kg；隔日一次；持续24天）后，肿瘤生长和侵袭被显著抑制[6]。AR-V7过表达的异种移植小鼠经腹腔注射ISA-2011B（40mg/kg；隔日一次；持续15天）后，肿瘤侵袭性生长受到抑制，ISA-2011B破坏了PIP5K1α依赖的AR-V7蛋白稳定性[7]。
| Cell experiment [1]: | |
Cell lines | C4-2 cells |
Preparation Method | ISA-2011B was dissolved in 0.1% DMSO to a final concentration of 50µM and used to treat C4-2 cells for 48 hours. Briefly, 5×103 viable cells were seeded in 100µl RPMI-1640 medium supplemented with 10% FBS, 1% PSN, and 2mM L-glutamine in a 96-well plate. After 48 hours, 20µl of MTS reagent was added to the medium and incubated for an additional 1 hour in the dark. The absorbance of colored methylene dye products produced by metabolically active living cells was measured at 490nm using a microplate reader. |
Reaction Conditions | 50μM; 48h |
Applications | ISA-2011B significantly inhibited the proliferation of C4-2 cells. |
| Animal experiment [2]: | |
Animal models | BALB/c nude mice |
Preparation Method | MDA-MB-231 cells (4×106) were implanted subcutaneously into the female BALB/c nude mice at the age of 8-12 weeks. After the mean tumor volumes reached 50mm3, the mice were randomly assigned into three different groups (6mice/group). The three groups of mice were treated with vehicle (control), docetaxel (10mg/kg) and ISA-2011B (40mg/kg), respectively, by intraperitoneal injection once every other day. The body weight and tumor diameters were measured every other day. The tumor volume was calculated with tumor diameters using the equation (a × b2/2, where a and b represent the larger and smaller diameters, respectively). After the treatment was completed, the mice were sacrificed and the tumors were collected for analysis. |
Dosage form | 40mg/kg; once every other day for 24 days; i.p. |
Applications | ISA-2011B treatment significantly inhibited tumor growth and invasion in the xenograft tumor mouse models. |
References: | |
| Cas No. | 1395347-24-6 | SDF | |
| Canonical SMILES | O=C(N1[C@H](C2=CNC3=C2C=C(Cl)C=C3)C4=C(C=C5C(OCO5)=C4)C[C@]16[H])CN(C)C6=O | ||
| 分子式 | C22H18ClN3O4 | 分子量 | 423.85 |
| 溶解度 | DMSO : ≥ 57 mg/mL (134.48 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3593 mL | 11.7966 mL | 23.5933 mL |
| 5 mM | 0.4719 mL | 2.3593 mL | 4.7187 mL |
| 10 mM | 0.2359 mL | 1.1797 mL | 2.3593 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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，
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 saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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- Purity: >99.50%
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