M3814 (nedisertib)
(Synonyms: M3814) 目录号 : GC32718
M3814 (nedisertib)是一种新型的、具有口服活性的DNA依赖性蛋白激酶（DNA-PK）抑制剂，M3814可抑制DNA-PK的活性来阻断DNA损伤修复通路。
Cas No.:1637542-33-6
Sample solution is provided at 25 µL, 10mM.
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M3814 (nedisertib) is a novel, orally active DNA-dependent protein kinase (DNA-PK) inhibitor. M3814 blocks the DNA damage repair pathway by inhibiting DNA-PK activity[1-2]. M3814 enhances the accumulation of DNA double-strand breaks, thereby increasing tumor cell sensitivity to radiotherapy. M3814 is primarily used in studies related to solid tumors and combination therapy with radiation[3-4].
In vitro, U251 glioblastoma cell lines were treated with M3814 (30-1000nM) for 24 hours, followed by ionizing radiation. When the concentration was greater than 300nM, M3814 significantly inhibited DNA-PKcs autophosphorylation, enhanced radiation-induced cell killing effects, and delayed the disappearance of γH2AX foci[5]. In non-small cell lung cancer NCI-H460/MX20 and A549/MX10 cell lines, pretreatment with M3814 (0.3-1μM) for 2 hours, followed by incubation with anticancer drugs for 72 hours, M3814 inhibited the ABCG2 efflux pump function, increased the intracellular accumulation of anticancer drugs[6].
In vivo, normal FVB mice underwent hemibrain irradiation (30Gy in 5 fractions) followed by a single oral dose of M3814 (60mg/kg) administered 10 minutes after irradiation. Drug distribution was measured at 2 and 5 hours post-irradiation, and radiation failed to effectively enhance the distribution of M3814 within the tumors[7]. In a BALB/c mouse model with subcutaneous CT26 colorectal cancer xenografts, oral administration of M3814 (50mg/kg) combined with standard of care (SOC) (Capecitabine 100mg/kg and 2Gy irradiation; 5 times per week for 2 weeks), M3814 significantly improved the clinical complete response rate compared to SOC alone. However, no significant difference in pathological complete response was observed between SOC plus M3814 and SOC alone[8].
References:
[1] Wise HC, Iyer GV, Moore K, et al. Activity of M3814, an Oral DNA-PK Inhibitor, In Combination with Topoisomerase II Inhibitors in Ovarian Cancer Models. Sci Rep. 2019 Dec 11;9(1):18882.
[2] Christner SM, Parise RA, Bakkenist CJ, et al. Quantitation of the DNA-dependent protein kinase inhibitor peposertib (M3814) and metabolite in human plasma by LC-MS/MS. Biomed Chromatogr. 2024 Dec;38(12):e6024.
[3] Zenke FT, Zimmermann A, Sirrenberg C, et al. Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models. Mol Cancer Ther. 2020 May;19(5):1091-1101.
[4] Wang M, Chen S, Wei Y, et al. DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer. Acta Pharm Sin B. 2021 Dec;11(12):3935-3949.
[5] Dragojevic S, Smith EJ, Regan MS, et al. DNA-PK Inhibition Shows Differential Radiosensitization in Orthotopic GBM PDX Models Based on DDR Pathway Deficits. Mol Cancer Ther. 2025 Jun 4;24(6):859-869.
[6] Wu ZX, Peng Z, Yang Y, et al. M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells. Front Oncol. 2020 May 12;10:674.
[7] Zhang W, Grams MP, Oberoi RK, et al. The impact of therapeutic radiation on drug distribution across the blood-brain barrier in normal mouse brain and orthotopic glioblastoma tumors. Neuro Oncol. 2025 Oct 14;27(9):2250-2261.
[8] Smithson M, Irwin RK, Williams G, et al. Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer. Neoplasia. 2022 Mar;25:53-61.
M3814 (nedisertib)是一种新型的、具有口服活性的DNA依赖性蛋白激酶（DNA-PK）抑制剂，M3814可抑制DNA-PK的活性来阻断DNA损伤修复通路[1-2]。M3814通过增强DNA双链断裂积累以增加肿瘤细胞对放射治疗的敏感性，M3814主要被用于实体瘤和与放射治疗联合的相关研究[3-4]。
在体外，M3814（30-1000nM）处理U251胶质母细胞瘤细胞系24小时，随后进行电离辐射处理。当浓度大于300nM时，M3814可显著抑制DNA-PKcs的自磷酸化，增强辐射诱导的细胞杀伤效应，并延迟γH2AX焦点在的消退[5]。M3814（0.3-1μM）预处理非小细胞肺癌NCI-H460/MX20和A549/MX10细胞系2小时，随后使用抗癌药孵育72小时。M3814可抑制ABCG2外排泵功能，增加抗癌药物在细胞内的积累[6]。
在体内，正常FVB小鼠经半脑照射（30Gy分5次）10分钟后，单次口服给药M3814（60mg/kg），在照射后2小时和5小时测量药物分布，辐射未能有效增强M3814在肿瘤内的分布[7]。在直肠癌CT26皮下移植瘤的BALB/c小鼠模型中，M3814（50mg/kg）口服给药与标准护理（Capecitabine 100mg/kg及2Gy照射；每周5次，持续2周）联合，与单独使用SOC相比，M3814联合SOC显著提高了临床完全缓解率。SOC联合M3814与单独使用SOC之间未观察到病理完全缓解的显著差异[8]。
| Cell experiment [1]: | |
Cell lines | NCI-H460, NCI-H460/MX20, A549, A549/MX10, HEK293/pcDNA3.1, HEK293/ABCG2, KB-3-1, and KB-C2 cells |
Preparation Method | Cells were maintained in Dulbecco's minimal essential medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin at 37°C, 5% CO₂. For reversal studies, ABCG2-overexpressing resistant cells (NCI-H460/MX20, A549/MX10) and transfected cells (HEK293/ABCG2) were treated with M3814 at non-toxic concentrations (0.3-1µM) for 2 hours prior to and during exposure to ABCG2 substrate drugs (mitoxantrone, doxorubicin). |
Reaction Conditions | 0.3-1μM; 2-hour pretreatment followed by co-incubation with chemotherapeutic agents for 72 hours. |
Applications | M3814 significantly reversed ABCG2-mediated multidrug resistance (MDR) by increasing the intracellular accumulation of substrate drugs in resistant cells. M3814 stimulated ABCG2 ATPase activity in a concentration-dependent manner |
| Animal experiment [2]: | |
Animal models | BALB/c mice with CT26 colorectal cancer subcutaneous xenografts |
Preparation Method | Mice were implanted with 1×10⁶ CT26 cells subcutaneously in the flank. When tumor volume reached 100mm³, mice were randomized into treatment groups: vehicle, standard of care (SOC; 100mg/kg capecitabine with 2Gy radiation), 50mg/kg M3814 with 2Gy radiation, and SOC plus 50mg/kg M3814. Capecitabine and/or M3814 were administered via oral gavage on radiation treatment days. Radiation (2Gy) was delivered daily, 5 days per week for 2 weeks. Mice were sacrificed one week after treatment completion for analysis. |
Dosage form | 50mg/kg; oral gavage; administered daily on radiation days (total 10 doses over 2 weeks). |
Applications | M3814 combined with SOC significantly increased the clinical complete response rate compared to SOC alone. no significant difference in pathological complete response was observed between SOC plus M3814 and SOC alone. M3814 effectively inhibited DNA-PK phosphorylation in tumors when combined with SOC treatment. |
References: | |
| Cas No. | 1637542-33-6 | SDF | |
| 别名 | M3814 | ||
| Canonical SMILES | COC1=CC=C([C@@H](O)C2=CC(C3=C(C=CC(N4CCOCC4)=C5)C5=NC=N3)=C(F)C=C2Cl)N=N1 | ||
| 分子式 | C24H21ClFN5O3 | 分子量 | 481.91 |
| 溶解度 | DMSO : 100 mg/mL (207.51 mM);Water : < 0.1 mg/mL (insoluble) | 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 | 2.0751 mL | 10.3754 mL | 20.7508 mL |
| 5 mM | 415 μL | 2.0751 mL | 4.1502 mL |
| 10 mM | 207.5 μL | 1.0375 mL | 2.0751 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。
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