6YKG

Structure-based exploration of selectivity for ATM inhibitors in Huntingtons disease

これはPDB形式変換不可エントリーです。

6YKG の概要

• エントリーDOI: 10.2210/pdb6ykg/pdb
• 分子名称: 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)
• 機能のキーワード: huntingtons disease; vps34, atm, lyase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 72932.21

構造登録者

Van de Poel, A.,Leonard, P.M.,Lamers, M.B.A.C. (登録日: 2020-04-06, 公開日: 2021-04-14, 最終更新日: 2024-01-24)

主引用文献

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

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: 33783225
DOI: 10.1021/acs.jmedchem.1c00114

実験手法

X-RAY DIFFRACTION (3.12 Å)