Scaffold modified Vemurafenib analogues as highly selective mitogen activated protein kinase kinase 4 (MKK4) inhibitors.

Hepatocytes / metabolism MAP Kinase Kinase 4 Vemurafenib / pharmacology
Acute and chronic liver failure Liver regeneration MKK4 inhibition NAFLD NASH Selectivity Vemurafenib α-carboline

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
05 Oct 2022
Historique:
received: 13 04 2022
revised: 29 06 2022
accepted: 02 07 2022
pubmed: 23 7 2022
medline: 17 8 2022
entrez: 22 7 2022
Statut: ppublish

Résumé

The mitogen-activated protein kinase kinase 4 (MKK4) has recently been identified as druggable target for the treatment of acute liver failure in RNAi experiments. In these experiments MKK4 was identified to be a major regulator in hepatocyte regeneration. Inhibitors thereof may serve as medication to promote liver regeneration or reducing hepatocyte death. Just a small number of potent inhibitors with acceptable selectivity towards relevant off-targets are known up to date. Among the known potent inhibitors, selectivity is highly sensitive towards minor modifications of the molecule, which makes it necessary to carefully balance between potency and selectivity. In the herein presented study, a new class of Vemurafenib-derived inhibitors was investigated with α-carbolines as new scaffold. This new scaffold showed a remarkable intrinsic selectivity towards the chosen off-targets, without affecting potency towards MKK4 on a broad range of structural modifications.

Identifiants

DOI: 10.1016/j.ejmech.2022.114584 PMID: 35868124
pubmed: 35868124
pii: S0223-5234(22)00486-X
doi: 10.1016/j.ejmech.2022.114584
pii:
doi:

Substances chimiques

Vemurafenib 207SMY3FQT
MAP Kinase Kinase 4 EC 2.7.12.2

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

114584

Informations de copyright

Copyright © 2022. Published by Elsevier Masson SAS.

Auteurs

Michael Juchum (M)

Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, DE, Germany.

Bent Pfaffenrot (B)

Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, DE, Germany.

Philip Klövekorn (P)

Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, DE, Germany.

Roland Selig (R)

Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, DE, Germany; HepaRegenix GmbH, Eisenbahnstraße 63, 72072, Tuebingen, Germany.

Wolfgang Albrecht (W)

HepaRegenix GmbH, Eisenbahnstraße 63, 72072, Tuebingen, Germany.

Lars Zender (L)

Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, 72076, Tuebingen, DE, Germany; Cluster of Excellence 'Image Guided and Functionally Instructed Tumor Therapies' (iFIT), Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.

Stefan A Laufer (SA)

Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, DE, Germany; Cluster of Excellence 'Image Guided and Functionally Instructed Tumor Therapies' (iFIT), Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany; Tuebingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, 72076, Tübingen, DE, Germany. Electronic address: stefan.laufer@uni-tuebingen.de.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Scaffold modified Vemurafenib analogues as...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › Mitogen-Activated Protein Kinase Kinases › MAP Kinase Kinase 4 › Scaffold modified Vemurafenib analogues as...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Indoles › Vémurafénib › Scaffold modified Vemurafenib analogues as...