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CAS No.: 1190932-38-7

COH29 Catalog No. CSN18928

Synonyms: RNR Inhibitor COH29

COH29 is a potent ribonucleotide reductase (RNR) inhibitor with anticancer activity with IC50 value of 8 μM in KB cell.

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400-920-2911

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靶点选择性

生物活性

实验方案

技术信息

生物活性

靶点 Ribonucleotide Reductase

IC50:8μM
描述The ribonucleotide reductase (RNR), the only enzyme responsible for the de novo conversion of ribonucleoside diphosphate (NDP) to deoxyribonucleoside diphosphate (dNDP), is the key regulator of intracellular dNTP (deoxyribonucleoside triphosphate) supply. RNR is an attractive target for anticancer agents given its central function in DNA synthesis, growth, metastasis, and drug resistance of cancer cells. Human RNR is composed of α subunits (RRM1) that contain the catalytic site and two binding sites for enzyme regulators, and β subunits (RRM2) with a binuclear iron co-factor that generates the stable tyrosyl radical necessary for catalysis. COH29 is a novel RNR inhibitor which acts as a potent inhibitor of both recombinant and cellular human RNR enzymes. COH29 inhibited recombinant RRM1/RRM2 activity in vitro with an IC₅₀ of 16 µM. COH29 interfered with RRM1-RRM2 binding in a dose-dependent manner. COH29 enhanced RRM1-RRM2 interaction at low dose (12.5 µM) but disrupted the complex at higher dose (> 25µM). In cultured KB human cancer cells, endogenously expressed RNR activity was approximately 50% decreased after 24 h incubation with 10 µM COH29. The IC₅₀ of COH29 is 8 µM in cell proliferation assays. Consistently, real-time KB cell growth was essentially halted by addition of 20 µM COH29 at 24 h. Impressive inhibition of most of the human cancer cell lines was observed in in vitro MTT cytotoxicity assays, with ovarian cancer and leukemia cells being the most sensitive to 10 µM COH29. In murine tumor xenograft models, COH29 resulted in a dose-dependent inhibition of MOLT-4 tumor xenograft growth with twice-daily oral dosing at 50 mg/kg and 100 mg/kg, which was pronounced by Day 12 of treatment^[3].
作用机制COH29 docks at pocket 5 of hRRM2 with the extra phenyl ring touching Gly233 as predicted. Mutagenesis studies confirmed residues Asp271, Tyr323, Phe326, Val327, and Met350 are involved in COH29 binding^[3].
临床研究

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT02112565	Unspecified Adult Solid Tumor,... more >> Protocol Specific Collapse <<	Phase 1	Recruiting	November 2019	United States, California ... more >> City of Hope Medical Center Recruiting Duarte, California, United States, 91010 Contact: Joseph Chao 626-471-9200 jchao@coh.org Principal Investigator: Joseph Chao Collapse <<

参考文献

[1] Chen MC, Zhou B, et al. The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro. Mol Pharmacol. 2015 Jun;87(6):996-1005.
[2] Zhou B, Su L, et al. A small-molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance. Cancer Res. 2013 Nov 1;73(21):6484-93.
[3] A Small-Molecule Blocking Ribonucleotide Reductase Holoenzyme Formation Inhibits Cancer Cell Growth and Overcomes Drug Resistance

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.3785 mL
- 11.8924 mL
- 23.7847 mL
- 5 mM
- 0.4757 mL
- 2.3785 mL
- 4.7569 mL
- 10 mM
- 0.2378 mL
- 1.1892 mL
- 2.3785 mL

技术信息

CAS号

1190932-38-7

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C22H16N2O5S

运输

蓝冰

分子量

420.44

别名

RNR Inhibitor COH29

溶解度

DMSO	77.0 mg/mL (183.1 mM)
Water	insoluble

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