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]。