4-(4-methyl-1,4-diazepan-1-yl)-N-[(5-methylpyrazin-2-yl)methyl]-8-oxo-11-thia-1,3-diazatetracyclo[8.7.0.0^{2,7}.0^{12,17}]heptadeca-2,4,6,9,12,14,16-heptaene-9-carboxamide

• ChemBase编号: 73128
• 分子式: C27H27N7O2S
• 平均质量: 513.61398
• 单一同位素质量: 513.19469414
• SMILES: c1c(nc2c(c1)c(=O)c(c1n2c2c(s1)cccc2)C(=O)NCc1cnc(cn1)C)N1CCN(CCC1)C
• Canonical SMILES: CN1CCCN(CC1)c1ccc2c(n1)n1c(c(c2=O)C(=O)NCc2cnc(cn2)C)sc2c1cccc2
• InChI: InChI=1S/C27H27N7O2S/c1-17-14-29-18(15-28-17)16-30-26(36)23-24(35)19-8-9-22(33-11-5-10-32(2)12-13-33)31-25(19)34-20-6-3-4-7-21(20)37-27(23)34/h3-4,6-9,14-15H,5,10-13,16H2,1-2H3,(H,30,36)
• InChIKey: XGPBJCHFROADCK-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 4-(4-methyl-1,4-diazepan-1-yl)-N-[(5-methylpyrazin-2-yl)methyl]-8-oxo-11-thia-1,3-diazatetracyclo[8.7.0.0^{2,7}.0^{12,17}]heptadeca-2,4,6,9,12,14,16-heptaene-9-carboxamide
• IUPAC传统名: 4-(4-methyl-1,4-diazepan-1-yl)-N-[(5-methylpyrazin-2-yl)methyl]-8-oxo-11-thia-1,3-diazatetracyclo[8.7.0.0^{2,7}.0^{12,17}]heptadeca-2,4,6,9,12,14,16-heptaene-9-carboxamide
• 别名: CX-5461

登记号

• CAS号: 1138549-36-6
• PubChem SID: 162038048
• PubChem CID: 25257557

理论计算性质

• Acid pKa: 12.576107
• 质子受体: 8
• 质子供体: 1
• LogD (pH = 5.5): 0.23223774
• LogD (pH = 7.4): 1.94163
• Log P: 2.424209
• 摩尔折射率: 155.107 cm^3
• 极化性: 54.531456 Å^3
• 极化表面积: 94.56 Å^2
• 可自由旋转的化学键: 4
• 里宾斯基五规则: false

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: DNA/RNA synthesis

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S2684

Biological Activity

• Description: CX-5461 selectively inhibits Pol I-driven transcription of rRNA with IC50 of 142 nM in HCT-116 cells.
• Targets: Pol I; HCT-116; A375; MIA PaCa-2
• IC50: 142 nM; 167 nM (ED50); 58 nM (ED50); 74 nM (ED50) ^[1]
• In Vitro: CX-5461 is found to selectively inhibit rRNA synthesis (Pol I IC50=142 nM; Pol II IC50 > 25 μM; selectivity ~200-fold) in the HCT-116 cells. Selective inhibition of rRNA synthesis by CX-5461 is confirmed in two other human solid tumor cell lines; melanoma A375 (Pol I IC50 = 113 nM; Pol II IC50 > 25 μM) and pancreatic carcinoma MIA PaCa-2 (Pol I IC50=54 nM; Pol II IC50 ~25 mM). CX-5461 possesses 250- to 300-fold selectivity for inhibition of rRNA transcription versus DNA replication and protein translation. CX-5461 exhibits broad antiproliferative potency in a panel of cancer cell lines in human cancer cell lines, but has minimal effect on viability of nontransformed human cells. The median EC50 across all tested cell lines is 147 nM, yet all normal cell lines have EC50 values of approximately 5, 000 nM. Evaluation of the antiproliferative dose response for HCT-116, A375, and MIA PaCa-2 cell lines yield EC50 values of 167, 58, and 74 nM. CX-5461 induces autophagy and senescence in solid tumor cancer cells, rather than apoptosis, through a p53-independent process. ^[1]
• In Vivo: CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. CX-5461 demonstrates significant MIA PaCa-2 TGI with TGI equal to 69% on day 31, comparable to that of gemcitabine (63% TGI). Gemcitabine is a positive control which is administered intraperitoneally once every 3 days at 120 mg/kg. Likewise, CX- 5461 demonstrates significant A375 TGI with TGI equal to 79% on day 32. ^[1]

Protocol

• Protocol: Kinase Assay ^[1]
• 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, cellsare 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.
• Protocol: Cell Assay ^[1]
• Cell Lines: panel of cancer and normal cell lines
• Concentrations: 0 – 2 μM
• Incubation Time: 96 hours
• Methods: 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
• Protocol: Animal Study ^[1]
• Animal Models: 5 × 10^6 MIA Paca-2 and A375 cancer cells are subcutaneously inoculated in the right flank of 5- to 6- week-old female athymic mice
• Formulation: CX-5461 is dissolved in 50 mM NaH₂PO₄ (pH 4.5).
• Doses: 50 mg/kg
• Administration: CX-5461 is administered orally once daily or every 3 days.

References

• References: [1] Drygin D, et al, Cancer Res, 2011, 71(4), 1418-1430.

参考文献

• Drygin D, et al, Cancer Res, 2011, 71(4), 1418-1430.