Biological and structural investigation of tetrahydro-β-carboline-based selective HDAC6 inhibitors with improved stability

• DOI: 10.1016/j.ejmech.2024.116676
• Publication Date: 2024-07-14T05:09:37Z
• Authors: Simon Scheuerer; Lucia Motlova; Linda Schäker-Hübner; Andreas Sellmer; Felix Feller; Fabian J. Ertl; Pierre Koch; Finn K. Hansen; Cyril Barinka; Siavosh Mahboobi
• Keywords: HDAC6; Stereocenter; Derivative (finance)

Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) has provided many arguments for further clinical evaluation. By the substitution of acidic hydrogen 4 different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves hydrolytic stability inhibitor. Further asymmetric synthesis shown that (S)-configured inhibitors preferentially bind HDAC6. This led highly selective and potent methyl-substituted derivative S-29b, elicited a long-lasting tubulin hyperacetylation in MV4-11 cells. Finally, crystal structure HDAC6/S-29b complex mechanistic explanation high potency stereoselectivity synthesized compound series.