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

DOI: 10.3390/molecules25245962 DOI Help

Authors: Anne Wurzlbauer (Ludwig-Maximilians University) , Katharina Rüben (RWTH Aachen University) , Ece Gürdal (Martin Luther University Halle-Wittenberg) , Apirat Chaikuad (Buchmann Institute for Molecular Life Sciences (BMLS), Goethe-University Frankfurt) , Stefan Knapp (Buchmann Institute for Molecular Life Sciences (BMLS), Goethe-University Frankfurt) , Wolfgang Sippl (Martin Luther University Halle-Wittenberg) , Walter Becker (RWTH Aachen University) , Franz Bracher (Ludwig-Maximilians University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecules , VOL 25

State: Published (Approved)
Published: December 2020

Open Access Open Access

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.

Journal Keywords: alkaloid; harmine; DYRK1A; monoamine oxidase A; docking studies; co-crystallization; structure–activity relationships

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)


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