TY  - JOUR
A1  - Wurzlbauer, Anne
A1  - Rüben, Katharina
A1  - Gürdal, Ece
A1  - Chaikuad, Apirat
A1  - Knapp, Stefan
A1  - Sippl, Wolfgang
A1  - Becker, Walter
A1  - Bracher, Franz
T1  - How to separate kinase inhibition from undesired monoamine oxidase a inhibition - the development of the DYRK1A inhibitor AnnH75 from the alkaloid harmine
T2  - Molecules
N2  - 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.
KW  - DYRK1A
KW  - alkaloid
KW  - co-crystallization
KW  - docking studies
KW  - harmine
KW  - monoamine oxidase A
KW  - structure–activity relationships
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/57477
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-574774
SN  - 1420-3049
VL  - 25
IS  - Article 5962
PB  - MDPI
CY  - Basel
ER  -