339016-21-6Relevant articles and documents
INHIBITORS OF RAF KINASES
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Paragraph 00183-00185, (2021/04/30)
Provided herein are inhibitors of receptor tyrosine kinase effector, RAF, pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.
Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease
Van De Po?l, Amanda,Toledo-Sherman, Leticia,Breccia, Perla,Cachope, Roger,Bate, Jennifer R.,Angulo-Herrera, Ivan,Wishart, Grant,Matthews, Kim L.,Martin, Sarah L.,Peacock, Marcus,Barnard, Amy,Cox, Helen C.,Jones, Graham,McAllister, George,Vater, Huw,Esmieu, William,Clissold, Cole,Lamers, Marieke,Leonard, Philip,Jarvis, Rebecca E.,Blackaby, Wesley,Eznarriaga, Maria,Lazari, Ovadia,Yates, Dawn,Rose, Mark,Jang, Sung-Wook,Mu?oz-Sanjuan, Ignacio,Dominguez, Celia
, p. 5018 - 5036 (2021/05/04)
Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.
BIARYL AMIDE COMPOUNDS AS KINASE INHIBITORS
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Paragraph 0310; 0311, (2014/09/29)
The present invention provides compounds of Formula (I) as described herein, and salts thereof, and therapeutic uses of these compounds for treatment of disorders associated with Raf kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent.
