Design and synthesis of 1H-pyrazolo[3,4-b]pyridines targeting mitogen-activated protein kinase kinase 4 (MKK4) - A promising target for liver regeneration

Bent Pfaffenrot; Philip Klövekorn; Michael Juchum; Roland Selig; Wolfgang Albrecht; Lars Zender; Stefan A Laufer

doi:10.1016/j.ejmech.2021.113371

Design and synthesis of 1H-pyrazolo[3,4-b]pyridines targeting mitogen-activated protein kinase kinase 4 (MKK4) - A promising target for liver regeneration

Eur J Med Chem. 2021 Jun 5:218:113371. doi: 10.1016/j.ejmech.2021.113371. Epub 2021 Mar 17.

Authors

Bent Pfaffenrot¹, Philip Klövekorn¹, Michael Juchum¹, Roland Selig², Wolfgang Albrecht², Lars Zender³, Stefan A Laufer⁴

Affiliations

¹ Department of Pharmaceutical/Medicinal Chemistry an Tuebingen Center for Academic Drug Discovery (TüCAD(2)), Eberhard Karls Universität, Auf der Morgenstelle 8, 72076, Tübingen, DE, Germany.
² HepaRegenix GmbH, Eisenbahnstraße 63, 72072, Tübingen, DE, Germany.
³ 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.
⁴ Department of Pharmaceutical/Medicinal Chemistry an Tuebingen Center for Academic Drug Discovery (TüCAD(2)), Eberhard Karls Universität, 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. Electronic address: stefan.laufer@uni-tuebingen.de.

PMID: 33794385
DOI: 10.1016/j.ejmech.2021.113371

Abstract

Currently, the therapeutic options for treatment of liver failure are very limited. As mitogen-activated protein kinase kinase 4 (MKK4) has recently been identified by in vivo RNAi experiments to be a major regulator in hepatocyte regeneration, we pursued the development of a small molecule targeting this protein kinase. Starting from the approved BRAF^V600E inhibitor vemurafenib (8), that showed a high off-target affinity to MKK4 in an initial screening, we followed a scaffold-hopping approach, changing the core heterocycle from 1H-pyrrolo[2,3-b]pyridine to 1H-pyrazolo[2,3-b]pyridine (10). Affinity to MKK4 could be conserved while the selectivity against off-target protein kinases was slightly improved. Further modifications led to 58 and 59 showing high affinity to MKK4 in the low nanomolar range and excellent selectivity profile from mandatory multiparameter-optimization for the essential anti-targets (MKK7, JNK1) and off-targets (BRAF, MAP4K5, ZAK) in the MKK4 pathway. Herein we report the first selective MKK4 inhibitors in this class.

Keywords: 1H-pyrazolo[2,3-b]pyridine; Kinase inhibition; Liver failure; MKK4; NAFLD; Scaffold hopping.

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Humans
Liver Regeneration / drug effects*
MAP Kinase Kinase 4 / antagonists & inhibitors*
MAP Kinase Kinase 4 / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

1H-pyrazolo(3,4-b)pyridine
Protein Kinase Inhibitors
Pyrazoles
Pyridines
MAP Kinase Kinase 4
MAP2K4 protein, human