Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
22 10 2020
22 10 2020
Historique:
pubmed:
8
10
2020
medline:
29
12
2020
entrez:
7
10
2020
Statut:
ppublish
Résumé
Hetero-bifunctional PROteolysis TArgeting Chimeras (PROTACs) represent a new emerging class of small molecules designed to induce polyubiquitylation and proteasomal-dependent degradation of a target protein. Despite the increasing number of publications about the synthesis, biological evaluation, and mechanism of action of PROTACs, the characterization of the pharmacokinetic properties of this class of compounds is still minimal. Here, we report a study on the metabolism of a series of 40 PROTACs in cryopreserved human hepatocytes at multiple time points. Our results indicated that the metabolism of PROTACs could not be predicted from that of their constituent ligands. Their linkers' chemical nature and length resulted in playing a major role in the PROTACs' liability. A subset of compounds was also tested for metabolism by human cytochrome P450 3A4 (CYP3A4) and human aldehyde oxidase (
Identifiants
pubmed: 33026811
doi: 10.1021/acs.jmedchem.0c00793
pmc: PMC8015227
doi:
Substances chimiques
Antineoplastic Agents
0
Small Molecule Libraries
0
Cytochrome P-450 CYP3A
EC 1.14.14.1
CYP3A4 protein, human
EC 1.14.14.55
Aldehyde Oxidase
EC 1.2.3.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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