6YKG
Structure-based exploration of selectivity for ATM inhibitors in Huntingtons disease
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Summary for 6YKG
| Entry DOI | 10.2210/pdb6ykg/pdb |
| Descriptor | Phosphatidylinositol 3-kinase catalytic subunit type 3, 4-morpholin-4-yl-6-[(2~{R})-2-(phenylmethyl)pyrrolidin-1-yl]-1~{H}-pyridin-2-one (3 entities in total) |
| Functional Keywords | huntingtons disease; vps34, atm, lyase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 72932.21 |
| Authors | Van de Poel, A.,Leonard, P.M.,Lamers, M.B.A.C. (deposition date: 2020-04-06, release date: 2021-04-14, Last modification date: 2024-01-24) |
| Primary citation | Van de Poel, A.,Toledo-Sherman, L.,Breccia, P.,Cachope, R.,Bate, J.R.,Angulo-Herrera, I.,Wishart, G.,Matthews, K.L.,Martin, S.L.,Peacock, M.,Barnard, A.,Cox, H.C.,Jones, G.,McAllister, G.,Vater, H.,Esmieu, W.,Clissold, C.,Lamers, M.,Leonard, P.,Jarvis, R.E.,Blackaby, W.,Eznarriaga, M.,Lazari, O.,Yates, D.,Rose, M.,Jang, S.W.,Munoz-Sanjuan, I.,Dominguez, C. Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease. J.Med.Chem., 64:5018-5036, 2021 Cited by PubMed Abstract: 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., ) 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. PubMed: 33783225DOI: 10.1021/acs.jmedchem.1c00114 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.12 Å) |
Structure validation
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