CX-5461

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]。