How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition-The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine.

Anne Wurzlbauer,Apirat Chaikuad,Ece Gürdal,Wolfgang Sippl,Katharina Rüben,Franz Bracher,Stefan Knapp,Walter Becker

doi:10.3390/molecules25245962

Abstract

The β-carboline alkaloid harmine is a potent DYRK1A inhibitor, but suffers from undesired potent inhibition of MAO-A, which strongly limits its application. We synthesized more than 60 analogues of harmine, either by direct modification of the alkaloid or by de novo synthesis of β-carboline and related scaffolds aimed at learning about structure–activity relationships for inhibition of both DYRK1A and MAO-A, with the ultimate goal of separating desired DYRK1A inhibition from undesired MAO-A inhibition. Based on evidence from published crystal structures of harmine bound to each of these enzymes, we performed systematic structure modifications of harmine yielding DYRK1A-selective inhibitors characterized by small polar substituents at N-9 (which preserve DYRK1A inhibition and eliminate MAO-A inhibition) and beneficial residues at C-1 (methyl or chlorine). The top compound AnnH75 remains a potent DYRK1A inhibitor, and it is devoid of MAO-A inhibition. Its binding mode to DYRK1A was elucidated by crystal structure analysis, and docking experiments provided additional insights for this attractive series of DYRK1A and MAO-A inhibitors.

Highlights

Protein phosphorylation is a major regulatory mechanism of nearly every cellular process, and many human diseases involve aberrant protein kinase activities
In the course of a systematic modification ofof harmine, functionalizations of the native alkaloid werewere performed in a first harmine,easy-to-perform easy-to-performdirect direct functionalizations of the native alkaloid performed in aseries first ofseries synthesized analogues, typically by ring halogenation reactions, modification of the
The The β-carboline alkaloid harmine is a potent processes, certain certaincancers, cancers,diabetes, diabetes, and other diseases β–carboline alkaloid harmine is a inhibitor, but it suffers from undesired strong inhibition of monoamine oxidase A (MAO-A), which would potent DYRK1A inhibitor, but it suffers from undesired strong inhibition of MAO-A, whichprevent would application as a drug as anorinvestigative inhibitor in vivo

Summary

Introduction

Protein phosphorylation is a major regulatory mechanism of nearly every cellular process, and many human diseases involve aberrant protein kinase activities. Specific kinase inhibitors serve as valuable research tools to elucidate the individual roles of the more than 500 human protein kinases in physiological and pathological processes. Is a protein kinase that has important functions in neuronal development and cell cycle control, and attracts increasing attention as a possible drug target [1,2]. DYRK1A has been implicated in neurodegenerative processes [4], certain cancers [5] and regulation of pancreatic β-cell proliferation, suggesting inhibition of DYRK1A as a novel therapeutic strategy in diabetes [6,7]. Inhibitors of DYRK1A are of interest as chemical probes for the functional characterization of DYRK1A’s role in these pathological processes and as potential therapeutics

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