TDRL-551
目录号 : GC64542
TDRL-551是一种有效的复制蛋白A（RPA）抑制剂，IC50值为18µM。
Cas No.:1644626-43-6
Sample solution is provided at 25 µL, 10mM.
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TDRL-551 is a potent inhibitor of replication protein A (RPA) with an IC50 value of 18µM[1]. RPA is an important single-stranded DNA (ssDNA) binding protein complex in eukaryotes and plays an important role in multiple key biological processes such as DNA replication, repair, damage response, telomere maintenance and viral defense[2, 3]. TDRL-551 can inhibit RPA-DNA interaction and improve the efficacy of platinum-based chemotherapy for lung and ovarian cancer[4].
In vitro, TDRL-551 (0-200μM) treatment of H460, SKOV-3, A2780 and OVCA-429 cells for 48h inhibited cell viability in a dose-dependent manner[1]. TDRL-551 (0-20μM) treatment of human non-small cell lung cancer cell line H460 cells for 24h induced cell death in a dose-dependent manner, but without caspase activation, indicating that TDRL-551-induced cell death is a non-apoptotic mechanism[5].
In vivo, TDRL-551 (200mg/kg) was intraperitoneally injected into mice bearing non-small cell lung cancer (NSCLC) cell xenografts for 20 days, significantly inhibiting tumor growth in the mice, with an effect comparable to that of carboplatin. The combination of the two had a better effect[6].
References:
[1] Mishra A K, Dormi S S, Turchi A M, et al. Chemical inhibitor targeting the replication protein A–DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer[J]. Biochemical pharmacology, 2015, 93(1): 25-33.
[2] Dueva R, Iliakis G. Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond[J]. NAR cancer, 2020, 2(3): zcaa022.
[3] Zou Y U E, Liu Y, Wu X, et al. Functions of human replication protein A (RPA): from DNA replication to DNA damage and stress responses[J]. Journal of cellular physiology, 2006, 208(2): 267-273.
[4] Gavande N S, VanderVere-Carozza P S, Hinshaw H D, et al. DNA repair targeted therapy: The past or future of cancer treatment?[J]. Pharmacology & therapeutics, 2016, 160: 65-83.
[5] VanderVere-Carozza P S, Gavande N S, Jalal S I, et al. In vivo targeting replication protein A for cancer therapy[J]. Frontiers in Oncology, 2022, 12: 826655.
[6] Mishra A K. Developing small molecule inhibitors targeting Replication Protein A for platinum-based combination therapy[D]. , 2014.
TDRL-551是一种有效的复制蛋白A（RPA）抑制剂，IC50值为18µM[1]。RPA是真核生物中一种重要的单链DNA（ssDNA）结合蛋白复合物，在DNA复制、修复、损伤应答、端粒维持及病毒防御等多个关键生物学过程中发挥重要作用[2, 3]。TDRL-551能够抑制RPA-DNA相互作用，提高以铂为基础的肺癌和卵巢癌化疗的疗效[4]。
在体外，TDRL-551（0-200μM）处理H460、SKOV-3、A2780和OVCA-429细胞48h，均以剂量依赖性方式抑制了细胞的活力[1]。TDRL-551（0-20μM）处理人非小细胞肺癌细胞系H460细胞24h，以剂量依赖性方式诱导了细胞死亡，但没有伴随胱天蛋白酶活化，表明TDRL-551诱导的细胞死亡是一种非凋亡机制[5]。
在体内，TDRL-551（200mg/kg）通过腹腔注射治疗非小细胞肺癌（NSCLC）细胞异种移植的小鼠20天，显著抑制了小鼠体内肿瘤的生长，效果与卡铂（Carboplatin）相当，二者联合治疗效果更好[6]。
| Cell experiment [1]: | |
Cell lines | H460 cells |
Preparation Method | H460 cells were plated at 5×103 cells/well in black 96-well plates with clear bottoms (Costar) and incubated for 24h prior to treatments. Cells were treated with 0-20μM TDRL-551 for 24h. Apoptosis induction was determined by activation of Caspases 3 and 7 using the CellEvent™ Caspase-3/7 Green Detection Reagent (Invitrogen). |
Reaction Conditions | 0-20μM; 24h |
Applications | TDRL-551-induced cell death was not accompanied by caspase activation, suggesting that cell death is a non-apoptotic mechanism. |
| Animal experiment [2]: | |
Animal models | NOD/SCID mice |
Preparation Method | Sixty mice aged 8-10 weeks were implanted in the hind flank with 2×106 H460 NSCLC cells in Matrigel. Tumor volume was measured with a caliper. Eight days after implantation, mice with tumor sizes ranging from 32-152.5mm3 were randomized into four treatment groups. Carboplatin was dissolved in water and administered intraperitoneally at a dose of 50mg/kg on days 8, 14, and 20 after implantation. TDRL-551 was suspended in 20% DMSO, 10% Tween 80, and 70% PBS and injected intraperitoneally at a dose of 200mg/kg on days 8, 10, 14, 17, and 20. The control group was a group that did not receive the designated treatment. Tumor volume was monitored every two weeks and the results are expressed as the mean tumor volume ± standard error of the mean for each group. |
Dosage form | 200mg/kg; on days 8, 10, 14, 17, 20; i.p. |
Applications | Carboplatin treatment and TDRL-551 showed similar tumor growth inhibition effects. The difference in tumor volume between the combination treatment and TDRL-551 monotherapy was statistically significant at all data points after day 14. |
References: | |
| Cas No. | 1644626-43-6 | SDF | Download SDF |
| 分子式 | C25H23ClIN3O4 | 分子量 | 591.83 |
| 溶解度 | DMSO : 62.5 mg/mL (105.60 mM; Need ultrasonic) | 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 | 1.6897 mL | 8.4484 mL | 16.8967 mL |
| 5 mM | 0.3379 mL | 1.6897 mL | 3.3793 mL |
| 10 mM | 0.169 mL | 0.8448 mL | 1.6897 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet