FEN1-IN-SC13 is a small molecule inhibitor specifically targeting flap structure-specific endonuclease 1 (FEN1)[1]. FEN1-IN-SC13 demonstrates significant potential in the field of antitumor drug development[2].
In vitro, treatment of TC-YIK cells (a small cell neuroendocrine carcinoma of the cervix cell line) with 40μM FEN1-IN-SC13 for 48–72 hours significantly inhibited tumor cell proliferation and colony formation, and induced apoptosis and G2/M phase arrest[3]. Pre-treatment of breast cancer MCF7 cells, MDA-MB-231 cells, and various other tumor cell lines with 5–50μM FEN1-IN-SC13 specifically inhibits the flap endonuclease activity of FEN1, interfering with Okazaki fragment maturation and long-patch base excision repair. This leads to DNA replication blockage, accumulation of double-strand breaks, and subsequently induces G1 phase cell cycle arrest, chromosomal instability, and apoptosis[4].
In vivo, intraperitoneal injection of 5mg/kg FEN1-IN-SC13 every other day, combined with intravenous infusion of MSLN CAR-T cells (5×10⁶cells per mouse) in tumor-bearing B-NDG mice (subcutaneously inoculated with HeLa cells), FEN1-IN-SC13 significantly promoted CAR-T cell infiltration into solid tumors and enhanced antitumor activity without causing significant systemic toxicity[5]. Daily intraperitoneal injection of 200μg FEN1-IN-SC13 for 5 consecutive days, combined with local ionizing radiation (IR, 10Gy) in tumor-bearing nude mice (subcutaneously inoculated with HeLa cells), FEN1-IN-SC13 significantly suppressed tumor growth and enhanced radiosensitivity without inducing notable systemic toxicity[6].
References:
[1] Wang Z, Yong C, Fu Y, et al. Inhibition of FEN1 promotes DNA damage and enhances chemotherapeutic response in prostate cancer cells. Med Oncol. 2023 Jul 15;40(8):242.
[2] He L, Yang H, Zhou S, et al. Synergistic antitumor effect of combined paclitaxel with FEN1 inhibitor in cervical cancer cells. DNA Repair (Amst). 2018 Mar;63:1-9.
[3] Liu J, Zhong M, Yang K, et al. Proteomics analysis reveals FEN1 as a promising therapeutic target against small cell neuroendocrine carcinoma of the cervix. Sci Rep. 2025 Jul 30;15(1):27827.
[4] He L, Zhang Y, Sun H, et al. Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression. EBioMedicine. 2016 Dec;14:32-43.
[5] Dong Y, Wang Y, Yin X, et al. FEN1 inhibitor SC13 promotes CAR-T cells infiltration into solid tumours through cGAS-STING signalling pathway. Immunology. 2023 Nov;170(3):388-400.
[6] Li JL, Wang JP, Chang H, et al. FEN1 inhibitor increases sensitivity of radiotherapy in cervical cancer cells. Cancer Med. 2019 Dec;8(18):7774-7780.
FEN1-IN-SC13是一种特异性靶向DNA片段化内切酶1(FEN1)的小分子抑制剂[1]。FEN1-IN-SC13在抗肿瘤药物开发领域具有重要潜力[2]。
在体外，FEN1-IN-SC13（40μM）处理宫颈小细胞神经内分泌癌（SCNECC）TC-YIK细胞48–72小时，FEN1-IN-SC13显著抑制肿瘤细胞增殖与克隆形成，诱导细胞凋亡与G2/M期阻滞[3]。FEN1-IN-SC13（5–50μM）预处理乳腺癌MCF7细胞、MDA-MB-231细胞及多种肿瘤细胞，通过特异性抑制FEN1的瓣状内切酶活性，干扰Okazaki片段成熟和长片段碱基切除修复，导致DNA复制受阻和双链断裂积累，从而诱导细胞周期G1期阻滞、染色体不稳定性和凋亡[4]。
在体内，FEN1-IN-SC13（5mg/kg）隔日腹腔注射，用于处理荷瘤B-NDG小鼠（皮下接种HeLa细胞），联合MSLN CAR-T细胞（5×10细胞/只）静脉输注。FEN1-IN-SC13显著促进CAR-T细胞向实体瘤浸润并增强其抗肿瘤活性，同时未引起明显系统毒性[5]。FEN1-IN-SC13（200μg）每日腹腔注射连续5天，联合局部电离辐射（IR，10Gy）处理荷瘤裸鼠（皮下接种HeLa细胞），FEN1-IN-SC13显著抑制肿瘤生长并增强放疗敏感性，且未引起明显系统毒性[6]。