Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK.

Mike Bührmann,Julia Hardick,Matthias P Müller,Bianca M Wiedemann,Daniel Rauh,Maria Ecke,Kjetil Tasken

doi:10.1371/journal.pone.0184627

Abstract

In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38α MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38α MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography.

Highlights

Protein kinases have been a frequent topic in medicinal chemistry and drug development due to their key function as mediating components in signal transduction, regulating cellular pathways on a molecular level, thereby playing a crucial role in the emergence of several diseases
We recently identified a novel class of p38α MAPK binders addressing a C-terminal lipophilic binding pocket (LP) accessible for small molecules located at several angstroms distance from the enzymes active site
Starting from the crystal structures of 3 and 4 in complex with p38α (PDB-codes: 4DLI and 4DLJ) and some knowledge of the underlying binding mode, we employed a rational approach for the design and synthesis of new 4-amino-2-arylquinazolines

Summary

Introduction

Protein kinases have been a frequent topic in medicinal chemistry and drug development due to their key function as mediating components in signal transduction, regulating cellular pathways on a molecular level, thereby playing a crucial role in the emergence of several diseases. The conventional approach towards the treatment of kinase-related diseases has involved the administration of ATP-competitive inhibitors which potently occupy and thereby block the enzyme’s active site where the phosphotransfer from ATP to target substrates takes place [1, 2]. Development of selective inhibitors for a certain targeted kinase within the related members of this enzyme family remains a major hurdle in drug research [3, 4]. Successful strategies to gain improved selectivity within the kinome have revolved around employing unique structural features of individual kinases, such as covalent modification of cysteines [5, 6] or identifying and targeting alternative binding pockets distant from the active site [7]. Alternative bindings sites far from the ATP-pocket can directly regulate kinase affinity.

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Conclusion