Background
CX-5461 is a potent and orally bioavailable small-molecule inhibitor of rRNA synthesis that specifically inhibits RNA polymerase (Pol) I-driven transcription with IC50 value of 142 nM. CX-5461 exhibits antiproliferative?activity against human pancreatic tumor cells MIA Paca-2, human melanoma cells A375 and colorectal carcinoma cells?HCT-116 with EC50 values of 74, 58, and 167 nmol/L, respectively. [1].
CX-5461 was revealed to inhibit Pol I transcription via promoting the stabilization of p53. In addition, CX-5461 has been demonstrated to induce autophagy and senescence but not apoptosis in MIA Paca-2 and A375 cell lines.
In vivo, CX-5461 has shown to suppress tumor volume in both MIA Paca-2 and A375 derived xenograft mice models [1].
参考文献:
[1] Drygin D1,?Lin A,?Bliesath J,?Ho CB,?O'Brien SE,?Proffitt C,?Omori M,?Haddach M,?Schwaebe MK,?Siddiqui-Jain A,?Streiner N,?Quin JE,?Sanij E,?Bywater MJ,Hannan RD,?Ryckman D,?Anderes K,?Rice WG. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res.?2011 Feb 15;71(4):1418-30
Protocol
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Cell Experiments: [1]
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Cell lines
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hTERT-immortalized BJ-hTERT human fibroblasts, Human inflammatory breast cancer cell lines SUM 149PT and SUM 190PT, Human eosinophilic leukemia cell line EOL-1, human B cell precursor leukemia cell line SEM, and human acute monocytic leukemia cell line THP-1
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Preparation method
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Stored at room temperature as 10 mmol/L stock solutions in 50 mmol/L NaH2PO4?(pH 4.5)
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Reacting condition
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2 μmol/L, 1 hour
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Applications
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Treatment of HCT-116, A375, or MIA PaCa-2 with 2 μmol/L CX-5461 resulted in 40% to 60% reduction of the Pol I enzyme association with the rDNA promoter. CX-5461 significantly depleted the binding of Pol I transcription factors (TF) to the rDNA promoter in HCT-116 cells. In dose-response studies, the IC50?for inhibition of DNA synthesis in A375 and MIA PaCa-2 cell lines ranged from 16.8 to 27.9 μmol/L. Treatment of solid tumor cell lines with CX-5461 induced cellular senescence and autophagy through selective inhibition of rRNA synthesis. CX-5461 targets the SL1 transcription factor of the Pol I complex and induces autophagy and senescence among solid tumor cell lines and selectively kills cancer cells relative to normal cells.
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Animal experiment: [1]
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Animal models
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Murine xenograft models of human cancers, pancreatic carcinoma (MIA PaCa-2) and melanoma (A375)
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Dosage form
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Administered orally (50 mg/kg) either once daily or every 3 day
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Application
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In murine xenograft models bearing human melanoma cancers (A375), CX-5461 demonstrated significant TGI with TGI equal to 79% on day 32. Human solid tumors grown in murine xenograft models revealed that CX-5461 can be orally administered with favorable pharmacokinetics and an antitumor efficacy. CX-5461 was well tolerated at all tested schedules as judged by the absence of significant changes in animal body weights or overt toxicity.?
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
1. 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.
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