Discovery of selective TYK2 inhibitors: Design, synthesis, in vitro and in silico studies of promising hits with triazolopyrimidinone scaffold.

Autor: Istanbullu H; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Izmir Kâtip Celebi University, Cigli, Izmir, Turkey., Coban G; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey. Electronic address: gunes.coban@ege.edu.tr., Turunc E; Department of Biochemistry, Faculty of Pharmacy, Izmir Kâtip Celebi University, Cigli, Izmir, Turkey., Disel C; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey., Debelec Butuner B; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Jul; Vol. 148, pp. 107430. Date of Electronic Publication: 2024 May 07.
DOI: 10.1016/j.bioorg.2024.107430
Abstrakt: The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway mediates many cytokine and growth factor signals. Tyrosine kinase 2 (TYK2), one of the members of this pathway and the first described member of the JAK family. TYK2 associates with inflammatory and autoimmune diseases, cancer and diabetes. Here, we present novel compounds as selective inhibitors of the canonical kinase domain of TYK2 enzyme. These compounds were rationally designed and synthesized with appropriate reactions. Molecular modeling techniques were used to design and optimize the candidates for TYK2 inhibition and to determine the estimated binding orientations of them inside JAKs. Designed compounds potently inhibited TYK2 with good selectivity against other JAKs as determined by in vitro assays. In order to verify its selectivity properties, compound A8 was tested against 58 human kinases (KinaseProfiler™ assay). The effects of the selected seven compounds on the protein levels of members of the JAK/STAT family were also detected in THP-1 monocytes although the basal level of these proteins is poorly detectable. Therefore, their expression was induced by lipopolysaccharide treatment and compounds A8, A15, A18, and A19 were found to be potent inhibitors of the TYK2 enzyme, (9.7 nM, 6.0 nM, 5.0 nM and 10.3 nM, respectively), and have high selectivity index for the JAK1, JAK2, and JAK3 enzymes. These findings suggest that triazolo[1,5-a]pyrimidinone derivatives may be lead compounds for developing potent TYK2-selective inhibitors targeting enzymes' active site.
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 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: