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

Wurzlbauer, Anne; Rüben, Katharina; Gurdal, Enise Ece; Chaikuad, A.; Knapp, Stefan; Sippl, Wolfgang; Becker, Walter; Bracher, Franz

doi:10.3390/molecules25245962

Cited by 12 publications

(11 citation statements)

References 51 publications

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“… DYRK and CLK inhibitors. A few representative pharmacological inhibitors: AnnH75 [ 51 ], EGCG [ 255 ], EHT-1610 [ 55 ], Harmine [ 256 ], INDY [ 44 ], Leucettine L41 [ 43 , 257 ], Lorecivivint [ 258 , 259 ], GNF4877 [ 170 , 179 ], MU1210 [ 68 ], and TCMDC-135051 [ 251 , 252 ]. Numbers under each structure indicates IC50 values (expressed in µM) towards DYRK1A, CLK1, and GSK3β (33PanQinase™ assay, Reaction Biology Corp.).…”

Section: Figurementioning

confidence: 99%

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Lindberg

Meijer

2021

IJMS

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Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

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Section: Figurementioning

confidence: 99%

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Lindberg

Meijer

2021

IJMS

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“…In order to distinguish these two activities and to explore whether one of them is responsible for the effect of harmine on FOXO shuttling, we used specific chemical probes. Recently, distinctive changes at N-9 and C-1 have been introduced into the harmine molecule, resulting in AnnH75, a compound that preserves DYRK1A inhibition and eliminates MAO-A inhibition ( 16 ). We exposed U2foxRELOC cells to equal concentrations of harmine and AnnH75.…”

Section: Resultsmentioning

confidence: 99%

“…Rapamycin was purchased from LC Laboratories (Woburn, MA, USA); dihydroethidium, hydroxyurea, and phenformin hydrochloride were obtained from Sigma (St. Louis, MO, USA); and leptomycin B (LMB) was purchased from Alomone Labs (Jerusalem, Israel). AnnH75 was developed and synthesized in the Bracher Lab (Ludwig-Maximilians University, Munich, Germany) ( 16 ).…”

Section: Methodsmentioning

confidence: 99%

Screening Health-Promoting Compounds for Their Capacity to Induce the Activity of FOXO3

Jiménez

Silva

Calissi

et al. 2021

The Journals of Gerontology: Series A

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Several chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived β-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).

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“…Although harmine is a potent DYRK1A inhibitor, it also targets other DYRKs and monoamine oxidase (MAO-A), resulting in side effects that limit its therapeutic potential ( 102 ). To overcome this limitation, several derivatives of harmine are being synthesized that are more selective for DYRK1A ( 103 , 104 ).…”

Section: Introductionmentioning

confidence: 99%

The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target

et al. 2022

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Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a serine/threonine kinase that belongs to the DYRK family of proteins, a subgroup of the evolutionarily conserved CMGC protein kinase superfamily. Due to its localization on chromosome 21, the biological significance of DYRK1A was initially characterized in the pathogenesis of Down syndrome (DS) and related neurodegenerative diseases. However, increasing evidence has demonstrated a prominent role in cancer through its ability to regulate biologic processes including cell cycle progression, DNA damage repair, transcription, ubiquitination, tyrosine kinase activity, and cancer stem cell maintenance. DYRK1A has been identified as both an oncogene and tumor suppressor in different models, underscoring the importance of cellular context in its function. Here, we review mechanistic contributions of DYRK1A to cancer biology and its role as a potential therapeutic target.

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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

Cited by 12 publications

References 51 publications

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Screening Health-Promoting Compounds for Their Capacity to Induce the Activity of FOXO3

The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target

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