1403669-20-4Relevant articles and documents
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)
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.
Mycobacterium tuberculosis Decaprenylphosphoryl-β- d -ribose Oxidase Inhibitors: Expeditious Reconstruction of Suboptimal Hits into a Series with Potent in Vivo Activity
Borthwick, Jennifer A.,Alemparte, Carlos,Wall, Ian,Whitehurst, Benjamin C.,Argyrou, Argyrides,Burley, Glenn,De Dios-Anton, Paco,Guijarro, Laura,Monteiro, Maria Candida,Ortega, Fatima,Suckling, Colin J,Pichel, Julia Castro,Cacho, Monica,Young, Robert J.
, p. 2557 - 2576 (2020/03/31)
Decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) is an essential enzyme in Mycobacterium tuberculosis and has recently been studied as a potential drug target, with inhibitors progressing to clinical studies. Here we describe the identification of a n
Discovery of 4-morpholino-pyrimidin-6-one and 4-morpholino-pyrimidin-2-one- containing Phosphoinositide 3-kinase (PI3K) p110β isoform inhibitors through structure-based fragment optimisation
Giordanetto, Fabrizio,W?llberg, Andreas,Cassel, Johan,Ghosal, Saswati,Kossenjans, Michael,Yuan, Zhong-Qing,Wang, Xiaoping,Liang, Lifeng
, p. 6665 - 6670 (2013/01/14)
The discovery of 4-morpholino-pyrimidin-6-one and 4-morpholino-pyrimidin-2- one-containing inhibitors of Phosphoinositide 3-kinases (PI3K) p110β isoform is reported. Structure-based optimisation of the original fragment hit resulted in lead compounds with improvements in ligand efficiency, lipophilicity efficiency, p110β potency and selectivity over p110α.
