How to separate kinase inhibition from undesired monoamine oxidase a inhibition - the development of the DYRK1A inhibitor AnnH75 from the alkaloid harmine

  • 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.

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Author:Anne Wurzlbauer, Katharina Rüben, Ece Gürdal, Apirat ChaikuadORCiD, Stefan KnappORCiD, Wolfgang Sippl, Walter Becker, Franz BracherORCiDGND
Pubmed Id:
Parent Title (English):Molecules
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/12/16
Date of first Publication:2020/12/16
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/12/27
Tag:DYRK1A; alkaloid; co-crystallization; docking studies; harmine; monoamine oxidase A; structure–activity relationships
Issue:Article 5962
Page Number:34
Institutes:Biowissenschaften / Biowissenschaften
Medizin / Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0