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.