2. Academic Validation
  3. Biological and structural investigation of tetrahydro-β-carboline-based selective HDAC6 inhibitors with improved stability

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

  • Eur J Med Chem. 2024 Oct 5:276:116676. doi: 10.1016/j.ejmech.2024.116676.
Simon Scheuerer 1,  Lucia Motlova 2,  Linda Schäker-Hübner 3,  Andreas Sellmer 1,  Felix Feller 3,  Fabian J Ertl 4,  Pierre Koch 4,  Finn K Hansen 3,  Cyril Barinka 2,  Siavosh Mahboobi 5
Affiliations

Affiliations

  • 1 Institute of Pharmacy, Department of Pharmaceutical/Medicinal Chemistry I, University of Regensburg, 93040, Regensburg, Germany.
  • 2 Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50, Vestec, Czech Republic.
  • 3 Pharmaceutical Institute, Department of Pharmaceutical and Cell Biological Chemistry, University of Bonn, 53121, Bonn, Germany.
  • 4 Institute of Pharmacy, Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, 93040, Regensburg, Germany.
  • 5 Institute of Pharmacy, Department of Pharmaceutical/Medicinal Chemistry I, University of Regensburg, 93040, Regensburg, Germany. Electronic address: Siavosh.mahboobi@chemie.uni-regensburg.de.
PMID: 39067437 DOI: 10.1016/j.ejmech.2024.116676
Abstract

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

Keywords

Chemical structure; Enantiomers; HDAC selectivity; Histone deacetylase inhibitors; Phenylhydroxamate; Tetrahydro-β-carboline.

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