Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease
| Autor: | Sarah L. Martin, Dawn Yates, Grant Wishart, Ignacio Munoz-Sanjuan, Wesley Blackaby, Ovadia Lazari, Roger Cachope, Amanda Van de Poël, Leticia Toledo-Sherman, Esmieu William R K, Ivan Angulo-Herrera, Celia Dominguez, Rebecca E. Jarvis, Helen C. Cox, Amy Barnard, Graham Jones, Marcus Peacock, Sung-Wook Jang, Perla Breccia, Jennifer R. Bate, Cole Clissold, Philip Leonard, Maria Eznarriaga, Marieke Lamers, Mark Rose, George McAllister, Kim L. Matthews, Huw D. Vater |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Ataxia Pyridones Ataxia Telangiectasia Mutated Proteins Pyrimidinones Molecular Dynamics Simulation Crystallography X-Ray 01 natural sciences Morpholinos 03 medical and health sciences Chimera (genetics) Mice Structure-Activity Relationship Huntington's disease Drug Discovery medicine Animals Humans 030304 developmental biology Vacuolar protein sorting 0303 health sciences Binding Sites Chemistry Kinase fungi Autophagy Brain medicine.disease Class III Phosphatidylinositol 3-Kinases 0104 chemical sciences Mice Inbred C57BL 010404 medicinal & biomolecular chemistry Huntington Disease Biochemistry Drug Design Lipophilicity Molecular Medicine medicine.symptom Selectivity Half-Life |
| Zdroj: | Journal of medicinal chemistry. 64(8) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|