Covalent inhibition of histone deacetylase 8 by 3,4-dihydro-2H-pyrimido[1,2-c][1,3]benzothiazin-6-imine

• Published in: Biochimica et biophysica acta. General subjects Vol. 1863; no. 3; pp. 577 - 585
• Main Authors: Muth, Marius, Jänsch, Niklas, Kopranovic, Aleksandra, Krämer, Andreas, Wössner, Nathalie, Jung, Manfred, Kirschhöfer, Frank, Brenner-Weiß, Gerald, Meyer-Almes, Franz-Josef
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2019
• Subjects: active sites; Binding mechanism; childhood; computational methodology; Covalent inhibitor; crystal structure; Enzyme inhibition; HDAC8; histone deacetylase; Non-hydroxamate inhibitor; reaction mechanisms; reducing agents; Selective inhibition; sulfides; T-cell lymphoma; tandem mass spectrometry; therapeutics; thiocyanates; thiols; zinc; Enzyme inhibition; Non-hydroxamate inhibitor; Selective inhibition; Covalent inhibitor; HDAC8; Binding mechanism

HDAC8 is an established target for T-cell lymphoma and childhood neuroblastoma. Benzothiazine-imines are promising HDAC8 inhibitors with unknown binding mechanism lacking a usual zinc binding group. In this study high-resolution and quantitative HPLC-coupled ESI-MS/MS techniques are combined with cr...