CX-5461 is a potent and oral rRNA synthesis inhibitor. It inhibits RNA polymerase I-driven transcription of rRNA with IC50s of 142, 113, and 54 nM in HCT-116, A375, and MIA PaCa-2 cells, respectively[1]. CX-5461 is a DNA G-quadruplex stabilizer that is selectively lethal to BRCA1/2-deficient tumors[2].
In vitro, CX-5461 (2µM) was used to treat 50 human cancer cell lines and 5 non-transformed cell lines. The median EC50 for all cancer cell lines was 147 nM, while the EC50 value for all normal cell lines was approximately 5000nM, indicating that normal cells can tolerate the reduction of rRNA synthesis without inducing cell death[3]. CX-5461 (1.5µM) was used to treat PANC-1 cells for 24h, which inhibited cell migration and increased the expression of cadherin (CDH1) in cells[4]. Treatment of osteosarcoma MNNG and U2-OS cells with CX-5461 (0.01-10 µM) significantly reduced cell viability, induced G2 arrest and expression of microtubule-associated protein 1 light chain 3 II isoform[5].
In vivo, CX-5461 (125 mg/kg) was intraperitoneally injected into mice transplanted with MV 4;11 tumor cells for three weeks and showed effective antitumor activity, induced elevated p21 levels, and was well tolerated[6]. Oral administration of CX-5461 (40 mg/kg) to mice bearing ovarian cancer significantly inhibited tumor growth, reduced tumor volume, and increased γH2AX, a marker of DNA double-strand breaks in tumor cells[7].
References:
[1] Drygin D et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth[J].Cancer Res. 2011 Feb 15;71(4):1418-30.
[2]Xu H, Di Antonio M, McKinney S, et al. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours[J]. Nature communications, 2017, 8(1): 14432.
[3]Drygin D, Lin A, Bliesath J, et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth[J]. Cancer research, 2011, 71(4): 1418-1430.
[4]El Hassouni B, Mantini G, Immordino B, et al. CX-5461 inhibits pancreatic ductal adenocarcinoma cell growth, migration and induces DNA damage[J]. Molecules, 2019, 24(24): 4445.
[5]Li L, Li Y, Zhao J, et al. CX-5461 induces autophagy and inhibits tumor growth via mammalian target of rapamycin-related signaling pathways in osteosarcoma[J]. OncoTargets and therapy, 2016: 5985-5997.
[6]Bywater M J, Poortinga G, Sanij E, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53[J]. Cancer cell, 2012, 22(1): 51-65.
[7]Sanij E, Hannan K M, Xuan J, et al. CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer[J]. Nature communications, 2020, 11(1): 2641.
CX-5461是一种具口服活性的rRNA合成抑制剂，在HCT-116、A375和MIA PaCa-2细胞中，它抑制RNA聚合酶（RNA Pol）I驱动的rRNA转录，IC50分别为142、113和54nM[1]。CX-5461是一种DNA G四链体稳定剂，对BRCA1/2缺陷肿瘤具有选择性致死作用[2]。
在体外，CX-5461（2µM）处理50个人类癌细胞系和5个非转化细胞系，对所有癌细胞系的EC50中位数为147 nM，而对所有正常细胞系的EC50值约为 5000nM，说明正常细胞可以耐受rRNA合成的减少而不诱导细胞死亡[3]。CX-5461（1.5µM）处理PANC-1 细胞24h，抑制了细胞迁移，增加了细胞中钙粘蛋白（CDH1）的表达[4]。CX-5461（0.01-10µM）处理骨肉瘤MNNG和U2-OS细胞，显著降低细胞活力，诱导了细胞G2期阻滞和微管相关蛋白1轻链3 II亚型的表达[5]。
在体内，CX-5461（125mg/kg）通过腹腔注射治疗移植了MV 4;11肿瘤细胞的小鼠三周，表现出有效的抗肿瘤活性，诱导了p21水平升高，并且耐受性良好[6]。CX-5461（40mg/kg）通过口服治疗卵巢癌小鼠，显著抑制了肿瘤生长，减小了肿瘤体积，增加了肿瘤细胞的DNA双链断裂标志物γH2AX[7]。