Probing class I histone deacetylases (HDAC) with proteolysis targeting chimera (PROTAC) for the development of highly potent and selective degraders.

Autor: Ibrahim HS; Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt. Electronic address: hany.ibrahim@pharmazie.uni-halle.de., Guo M; Department of Natural Medicine, School of Pharmacy, Fudan University, Shanghai 201203, China; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, China., Hilscher S; Department of Enzymology, Institute of Biochemistry, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany., Erdmann F; Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany., Schmidt M; Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany., Schutkowski M; Department of Enzymology, Institute of Biochemistry, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany., Sheng C; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, China. Electronic address: shengcq@smmu.edu.cn., Sippl W; Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Dec; Vol. 153, pp. 107887. Date of Electronic Publication: 2024 Oct 12.
DOI: 10.1016/j.bioorg.2024.107887
Abstrakt: Class I HDACs are considered promising targets for cancer due to their role in epigenetic modifications. The main challenges in developing a new, potent and non-toxic class I HDAC inhibitor are selectivity and appropriate pharmacokinetics. The PROTAC technique (Proteolysis Targeting Chimera) is a new method in drug development for the production of active substances that can degrade a protein of interest (POI) instead of inhibiting it. This technique will open the era to produce selective and potent drugs with a high margin of safety. Previously, we reported different inhibitors targeting class I HDACs functionalized with aminobenzamide or hydroxamate groups. In the current research work, we will employ PROTAC technique to develop class I HDAC degraders based on our previously reported inhibitors. We synthesized two series of aminobenzamide-based PROTACs and hydroxamate-based PROTACs and tested them in vitro against class I HDACs. To ensure their degradation, all of them were screened against HDAC2 as representative example of class I. The best candidates were evaluated at different concentrations at various HDAC subtypes. This resulted in the PROTAC (32a) (HI31.1) that degrades HDAC8 with a DC 50 of 8.9 nM with a proper margin of selectivity against other isozymes. Moreover, PROTAC 32a is able to degrade HDAC6 with DC 50  = 14.3 nM. Apoptotic study on leukemic cells (MV-4-11) displayed more than 50 % apoptosis took place at 100 nM. PROTAC 32a (HI31.1) showed a good margin of safety against normal cell line and proper chemical stability.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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