Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents
| Autor: | Paul S.H. Wang, Michael O'donnell, Alistair Rutherford, John Pollard, Jean-Damien Charrier, Somhairle Maccormick, Ronald Knegtel, Philip Michael Reaper, David Kay, Joanne Pinder, Steven Durrant, Michael Mortimore, Stephen Clinton Young, Golec Julian M C |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular DNA damage Molecular Sequence Data Regulator Antineoplastic Agents Protein Serine-Threonine Kinases Substrate Specificity Structure-Activity Relationship chemistry.chemical_compound Catalytic Domain Drug Discovery medicine Structure–activity relationship Amino Acid Sequence Sulfones Protein kinase A Protein Kinase Inhibitors Kinase Drug discovery Cancer medicine.disease chemistry Biochemistry Pyrazines Cancer research Molecular Medicine DNA |
| Zdroj: | Journal of Medicinal Chemistry. 54:2320-2330 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K(i) of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC(50) of 0.42 μM. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation. |
| Databáze: | OpenAIRE |
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