- STRAD-BINDING AGENTS AND USES THEREOF
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Disclosed herein, inter alia, are compounds for binding STRAD pseudokinase and uses thereof.
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- Evaluation of [18F]-ATRi as PET tracer for in vivo imaging of ATR in mouse models of brain cancer
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Rationale Ataxia telangiectasia and Rad3-related (ATR) threonine serine kinase is one of the key elements in orchestrating the DNA damage response (DDR). As such, inhibition of ATR can amplify the effects of chemo- and radiation-therapy, and several ATR i
- Carlucci, Giuseppe,Carney, Brandon,Sadique, Ahmad,Vansteene, Axel,Tang, Jun,Reiner, Thomas
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula (IV): (Formula (IV)) wherein the variables are as defined herein.
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Page/Page column 37; 38-39
(2011/12/02)
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- Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents
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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 Ki of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC50 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.
- Charrier, Jean-Damien,Durrant, Steven J.,Golec, Julian M. C.,Kay, David P.,Knegtel, Ronald M. A.,MacCormick, Somhairle,Mortimore, Michael,O'Donnell, Michael E.,Pinder, Joanne L.,Reaper, Philip M.,Rutherford, Alistair P.,Wang, Paul S. H.,Young, Stephen C.,Pollard, John R.
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p. 2320 - 2330
(2011/06/17)
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