COH29 is an orally available, aromatically substituted thiazole and inhibitor of the human ribonucleotide reductase (RNR), with potential antineoplastic activity. Upon oral administration, the RNR inhibitor COH29 binds to the ligand-binding pocket of the RNR M2 subunit (hRRM2) near the C-terminal tail. This blocks the interaction between the hRRM1 and hRRM2 subunits and interferes with the assembly of the active hRRM1/hRRM2 complex of RNR. Inhibition of RNR activity decreases the pool of deoxyribonucleotide triphosphates available for DNA synthesis. The resulting decrease in DNA synthesis causes cell cycle arrest and growth inhibition. In addition, this agent may inhibit the nuclear enzyme poly (ADP-ribose) polymerase (PARP) 1, which prevents the repair of damaged DNA, and causes both the accumulation of single and double strand DNA breaks and the induction of apoptosis.
Chemical Formula: C22H16N2O5S
Exact Mass: 420.078
Molecular Weight: 420.439
Elemental Analysis: C, 62.85; H, 3.84; N, 6.66; O, 19.03; S, 7.63
Chemical Name: N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide
InChi Code: InChI=1S/C22H16N2O5S/c25-15-8-6-13(10-17(15)27)19-20(12-4-2-1-3-5-12)30-22(23-19)24-21(29)14-7-9-16(26)18(28)11-14/h1-11,25-28H,(H,23,24,29)
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
COH29 (RNR Inhibitor COH29) overcome hydroxyurea and gemcitabine resistance in cancer cells. It effectively inhibits proliferation of most cell lines in the NCI 60 human cancer panel, most notably ovarian cancer and leukemia, but exerts little effect on normal fibroblasts or endothelial cells. Site-directed mutagenesis, NMR and surface plasmon resonance biosensor studies confirm COH29 binding to the proposed ligand-binding pocket and offer evidence for assembly blockade of the RRM1-RRM2 quaternary structure.
COH29 results 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 is pronounced by Day 12 of treatment. Similarly, 7 days of treatment of mice bearing TOV11D xenografts with 200, 300, or 400 mg/kg/day COH29 results in a dose-dependent inhibition of tumor xenograft growth. Tumor growth is significantly inhibited compared with the control group.
Chen YR, Tsou B, Hu S, Ma H, Liu X, Yen Y, Ann DK. Autophagy induction causes a synthetic lethal sensitization to ribonucleotide reductase inhibition in breast cancer cells. Oncotarget. 2016 Jan 12;7(2):1984-99. doi: 10.18632/oncotarget.6539. PubMed PMID: 26675256; PubMed Central PMCID: PMC4811511.
Chen MC, Zhou B, Zhang K, Yuan YC, Un F, Hu S, Chou CM, Chen CH, Wu J, Wang Y, Liu X, Smith DL, Li H, Liu Z, Warden CD, Su L, Malkas LH, Chung YM, Hu MC, Yen Y. The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro. Mol Pharmacol. 2015 Jun;87(6):996-1005. doi: 10.1124/mol.114.094987. Epub 2015 Mar 26. PubMed PMID: 25814515; PubMed Central PMCID: PMC4429719.
Zhang H, Liu X, Warden CD, Huang Y, Loera S, Xue L, Zhang S, Chu P, Zheng S, Yen Y. Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in estrogen-negative breast cancers. BMC Cancer. 2014 Sep 11;14:664. doi: 10.1186/1471-2407-14-664. PubMed PMID: 25213022; PubMed Central PMCID: PMC4171582.
Zhou B, Su L, Hu S, Hu W, Yip ML, Wu J, Gaur S, Smith DL, Yuan YC, Synold TW, Horne D, Yen Y. 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. doi: 10.1158/0008-5472.CAN-13-1094. Epub 2013 Sep 26. PubMed PMID: 24072748; PubMed Central PMCID: PMC3823501.
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