4CBT

Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC inhibitors as a potential therapy for Huntington's disease

4CBT の概要

• エントリーDOI: 10.2210/pdb4cbt/pdb
• 関連するPDBエントリー: 4CBY
• 分子名称: HISTONE DEACETYLASE 4, (1R,2R,3R)-2-[4-(5-fluoranylpyrimidin-2-yl)phenyl]-N-oxidanyl-3-phenyl-cyclopropane-1-carboxamide, ZINC ION, ... (4 entities in total)
• 機能のキーワード: hydrolase, neurodegeneration, huntingtons disease, amyotrophic lateral sclerosis, muscle atrophy, class iia histone deacetylase inhibitors, sar, hydroxamic acid, cyclopropanation
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus: P56524
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 129833.44

構造登録者

Burli, R.W.,Luckhurst, C.A.,Aziz, O.,Matthews, K.L.,Yates, D.,Lyons, K.A.,Beconi, M.,McAllister, G.,Breccia, P.,Stott, A.J.,Penrose, S.D.,Wall, M.,Lamers, M.,Leonard, P.,Mueller, I.,Richardson, C.M.,Jarvis, R.,Stones, L.,Hughes, S.,Wishart, G.,Haughan, A.F.,O'Connell, C.,Mead, T.,McNeil, H.,Vann, J.,Mangette, J.,Maillard, M.,Beaumont, V.,Munoz-Sanjuan, I.,Dominguez, C. (登録日: 2013-10-16, 公開日: 2013-12-11, 最終更新日: 2024-05-08)

主引用文献

Burli, R.W.,Luckhurst, C.A.,Aziz, O.,Matthews, K.L.,Yates, D.,Lyons, K.A.,Beconi, M.,McAllister, G.,Breccia, P.,Stott, A.J.,Penrose, S.D.,Wall, M.,Lamers, M.,Leonard, P.,Muller, I.,Richardson, C.M.,Jarvis, R.,Stones, L.,Hughes, S.,Wishart, G.,Haughan, A.F.,O'Connell, C.,Mead, T.,McNeil, H.,Vann, J.,Mangette, J.,Maillard, M.,Beaumont, V.,Munoz-Sanjuan, I.,Dominguez, C.
Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease.
J. Med. Chem., 56:9934-9954, 2013

PubMed Abstract: Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.

PubMed: 24261862
DOI: 10.1021/jm4011884

実験手法

X-RAY DIFFRACTION (3.03 Å)