From off-to on-target: New BRAF-inhibitor-template-derived compounds selectively targeting mitogen activated protein kinase kinase 4 (MKK4).

Drug Discovery Humans MAP Kinase Kinase 4 / antagonists & inhibitors Protein Kinase Inhibitors / chemistry Proto-Oncogene Proteins B-raf / antagonists & inhibitors Vemurafenib / analogs & derivatives
Acute and chronic liver failure Inhibitors Liver failure Liver regeneration MEK4 MKK4 NAFLD NASH Vemurafenib

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:
15 Jan 2021
Historique:
received: 24 07 2020
revised: 19 10 2020
accepted: 20 10 2020
pubmed: 18 11 2020
medline: 29 4 2021
entrez: 17 11 2020
Statut: ppublish

Résumé

The mitogen-activated protein kinase (MAP) kinase 4 (MKK4) was found to be a major regulator of liver regeneration and could be a valuable drug target addressing liver related diseases by restoring its intrinsic regenerative capacity. We report on the synthesis and optimization of novel MKK4 inhibitors following a target-hopping strategy from the FDA-approved BRAF

Identifiants

DOI: 10.1016/j.ejmech.2020.112963 PMID: 33199152
pubmed: 33199152
pii: S0223-5234(20)30935-1
doi: 10.1016/j.ejmech.2020.112963
pii:
doi:

Substances chimiques

Protein Kinase Inhibitors 0
Vemurafenib 207SMY3FQT
Proto-Oncogene Proteins B-raf EC 2.7.11.1
MAP Kinase Kinase 4 EC 2.7.12.2

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

112963

Informations de copyright

Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SL is stock owner <3% of Heparegenix GmbH.However this relationship has not influenced any work related to this manuscript.

Auteurs

Philip Klövekorn (P)

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.

Michael Juchum (M)

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

Roland Selig (R)

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, 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.

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 › Techniques d'investigation › Développement de médicament › Découverte de médicament › From off-to on-target: New...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › From off-to on-target: New...
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 › From off-to on-target: New...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › From off-to on-target: New...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Kinases raf › Protéines proto-oncogènes B-raf › From off-to on-target: New...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Indoles › Vémurafénib › From off-to on-target: New...