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

S. Scheuerer, L. Motlova, L. Schäker-Hübner, A. Sellmer, F. Feller, FJ. Ertl, P. Koch, FK. Hansen, C. Barinka, S. Mahboobi

. 2024 ; 276 (-) : 116676. [pub] 20240726

Jazyk angličtina Země Francie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24018722

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.

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$a Sellmer, Andreas $u Institute of Pharmacy, Department of Pharmaceutical/Medicinal Chemistry I, University of Regensburg, 93040, Regensburg, Germany
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