SCR7 is a small molecule inhibitor of DNA Ligase IV [1] [2], which inhibits the non-homologous end-joining (NHEJ) pathway by binding to the DNA binding domain (DBD) of Ligase IV [3]. SCR7 is commonly used in cancer therapeutic research [4] and serves as a valuable tool for improving the efficiency of genome editing [5].
SCR7 exhibits concentration- and time-dependent cytotoxicity in DLBCL cells (SUDHL8) via both extrinsic and intrinsic apoptosis pathways. In SUDHL8 cells, treatment with SCR7 at 100 and 250µM for 48 and 72 hours increases mitochondrial membrane potential, causes translocation of phosphatidylserine to the cell surface, and raises the expression of double-strand break repair proteins and apoptotic markers [6].
SCR7 (10mg/kg, every alternate day for six doses, i.p.) treatment can significantly enhance the the effect of radiation in mice with Dalton's lymphoma (DLA) liquid tumors. The combination of SCR7 and ionizing radiation (IR) can markedly reduce tumor growth and improve the survival rate of tumor-bearing mice [7].
References:
[1]. Srivastava M, Nambiar M, Sharma S, et al. An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression. Cell. 2012 Dec 21;151(7):1474-87. doi: 10.1016/j.cell.2012.11.054.
[2]. Gkotzamanidou M, Terpos E, Bamia C, et al. DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7. Blood. 2016 Sep 1;128(9):1214-25. doi: 10.1182/blood-2016-01-691618. Epub 2016 Jul 21. PMID: 27443291; PMCID: PMC5524533.
[3]. Manjunath M, Choudhary B, Raghavan SC. SCR7, a potent cancer therapeutic agent and a biochemical inhibitor of nonhomologous DNA end-joining. Cancer Rep (Hoboken). 2021 Jun;4(3):e1341. doi: 10.1002/cnr2.1341. Epub 2021 Jan 26.
[4]. Vartak SV, Swarup HA, Gopalakrishnan V, et al. Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner. FEBS J. 2018 Nov;285(21):3959-3976. doi: 10.1111/febs.14661. Epub 2018 Oct 8. PMID: 30230716.
[5]. Hu Z, Shi Z, Guo X, Jiang B, Wang G, Luo D, Chen Y, Zhu YS. Ligase IV inhibitor SCR7 enhances gene editing directed by CRISPR-Cas9 and ssODN in human cancer cells. Cell Biosci. 2018 Feb 19;8:12. doi: 10.1186/s13578-018-0200-z. PMID: 29468011; PMCID: PMC5819182.
[6]. Gopalakrishnan V, Radha G, Raghavan SC, et al. Inhibitor of nonhomologous end joining can inhibit proliferation of diffuse large B-Cell lymphoma cells and potentiate the effect of ionization radiation. J Radiat Cancer Res 2018;9:93-101. DOI: 10.4103/jrcr.jrcr_9_18
[7]. Gopalakrishnan V, Sharma S, Ray U, et al. SCR7, an inhibitor of NHEJ can sensitize tumor cells to ionization radiation. Mol Carcinog. 2021 Sep;60(9):627-643. doi: 10.1002/mc.23329. Epub 2021 Jun 30.
SCR7是一种DNA连接酶IV的小分子抑制剂 [1] [2] ，通过结合连接酶IV的DNA结合域（DBD）来抑制非同源末端连接（NHEJ）途径 [3] 。SCR7常用于癌症治疗研究 [4] ，并且是提高基因组编辑效率的重要工具 [5] 。
SCR7在DLBCL细胞（SUDHL8）中表现出浓度和时间依赖的细胞毒性，作用途径包括外源性和内源性凋亡。SUDHL8细胞经100和250µM的SCR7处理48和72小时后，线粒体膜电位增加，磷脂酰丝氨酸转移到细胞表面，双链断裂修复蛋白和凋亡标志物的表达增加 [6] 。
SCR7（10mg/kg，每隔一天一次，共六次，腹腔注射）处理能够显著增强辐射对患有道尔顿淋巴瘤（DLA）液体肿瘤小鼠的效果。SCR7与电离辐射（IR）的联合使用可以显著减少肿瘤生长并提高带瘤小鼠的存活率 [7] 。