On October 22, 2020, Goracci, Laura; Desantis, Jenny; Valeri, Aurora; Castellani, Beatrice; Eleuteri, Michela; Cruciani, Gabriele published an article.Product Details of 1949837-12-0 The title of the article was Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications. And the article contained the following:
Hetero-bifunctional PROteolysis TArgeting Chimeras (PROTACs) represent a new emerging class of small mols. designed to induce polyubiquitylation and proteasomal-dependent degradation of a target protein. Despite the increasing number of publications about the synthesis, biol. 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’ chem. 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 P 450 3A4 (CYP3A4) and human aldehyde oxidase (hAOX) for more in-depth data interpretation, and both enzymes resulted in active PROTAC metabolism The experimental process involved the reaction of (2S,4R)-1-((2S)-2-(tert-butyl)-15-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-4,14-dioxo-6,10-dioxa-3,13-diazapentadecan-1-oyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(cas: 1949837-12-0).Product Details of 1949837-12-0
The Article related to protac metabolism human hepatocytes ligands linkers cyp3a4 haox, Pharmacology: Drug Metabolism and other aspects.Product Details of 1949837-12-0
Referemce:
1,2,3-Triazole – Wikipedia,
Triazoles – an overview | ScienceDirect Topics