CX-5461, a selective inhibitor of rRNA synthesis, suppresses Pol I-driven transcription of rRNA.

在异种移植人固体肿瘤的小鼠模型中,通过口服CX-5461(50 mg/kg)表现出抗实体瘤活性.

在HCT-116（EC50=167 nM）,A375（EC50=58 nM）,和MIA PaCa-2（和EC50=74 nM）细胞系中,CX-5461能够抑制细胞增殖。在固体肿瘤细胞中,CX-5461诱导细胞自噬或衰老,但不诱导细胞凋亡,其中qi黑色素瘤 A375 (Pol I IC50 = 113 nM；Pol II IC50 > 25 μM)和胰腺癌MIA PaCa-2 (Pol I IC50=54 nM；Pol II IC50 ~25 mM)。在HCT-116细胞中,CX-5461选择性抑制rRNA合成,Pol I（IC50=142 nM）,Pol II （IC50 > 25 μM）。

Pol I and Pol II Transcription Assay: Two short-lived RNA transcripts (half-lives ~20-30 minutes), one produced by Pol I and another by Pol II, are quantitated by qRT-PCR as a measure of CX-5461-related effects on transcription. The 45S pre-rRNA served as the Pol I transcript and the mRNA for the protooncogene c-myc served as the comparator Pol II transcript. Both Pol I and Pol II transcription are known to be affected by general cellular stress. To minimize the potential effects of such stress, cells are exposed to test agents for only a short period of time (2 hours). This is sufficient time for these transcripts to be reduced by greater than 90% if CX-5461 affects their synthesis.

Cells are plated on 96-well plates and treated the next day with dose response of CX-5461 for 96 hours. Cell viability is determined using Alamar Blue and CyQUANT assays(Only for Reference)

1138549-36-6

C27H27N7O2S

513.62

CX-5461

[1]Li, Dingfeng, Juan Zhang, Ming Wang, Xiaohui Li, Huarui Gong, Huiping Tang, Lin Chen, Lili Wan, and Qiang Liu. Activity dependent LoNA regulates translation by coordinating rRNA transcription and methylation[J]. Nature communications. 2018 Apr 30;9(1):1726. [2]Drygin D, et al, Cancer Res, 2011, 71(4), 1418-1430.

[1]Li, Dingfeng, Juan Zhang, Ming Wang, Xiaohui Li, Huarui Gong, Huiping Tang, Lin Chen, Lili Wan, and Qiang Liu. Activity dependent LoNA regulates translation by coordinating rRNA transcription and methylation. Nature Communications. 2018, 9(1): 1-14 [2]Fu Y, Liu Y, Wen T, et al. Real-time imaging of RNA polymerase I activity in living human cells. Journal of Cell Biology. 2022, 222(1): e202202110.

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