The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors
| Autor: | Steven M. Murphy, Bruce Sherf, Tom Dent, Daniel P. Silver, Andrew Bailey, L. Nathan Tumey, Jianmin Wang, Youssef L. Bennani, Elizabeth Ann Gleason, David C. Bom, Bayard Huck, Christina Leventhal, Sherry Boozer, John J. Harrington, Stephen Rundlett, Kurt R. Brunden |
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| Rok vydání: | 2004 |
| Předmět: |
Xeroderma pigmentosum
DNA repair DNA damage Flap Endonucleases Clinical Biochemistry Flap structure-specific endonuclease 1 Pharmaceutical Science Biochemistry Endonuclease chemistry.chemical_compound Structure-Activity Relationship Cell Line Tumor Drug Discovery medicine Temozolomide Humans Urea Enzyme Inhibitors Molecular Biology Xeroderma Pigmentosum biology Organic Chemistry Base excision repair medicine.disease Methyl Methanesulfonate Methyl methanesulfonate Dacarbazine chemistry Urinary Bladder Neoplasms biology.protein Molecular Medicine Nucleotide excision repair DNA Damage |
| Zdroj: | Bioorganicmedicinal chemistry letters. 15(2) |
| ISSN: | 0960-894X |
| Popis: | Flap endonuclease-1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. Sensitization to DNA damaging agents is a potential method for the improvement of the therapeutic window of traditional chemotherapeutics. In this paper, we describe the identification and SAR of a series of low nanomolar FEN1 inhibitors. Over 1000-fold specificity was achieved against a related endonuclease, xeroderma pigmentosum G (XPG). Two compounds from this series significantly potentiate the action of methyl methanesulfonate (MMS) and temozolamide in a bladder cancer cell line (T24). To our knowledge, these are the most potent endonuclease inhibitors reported to date. |
| Databáze: | OpenAIRE |
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