Development of DANDYs, New 3,5-Diaryl-7-azaindoles Demonstrating Potent DYRK1A Kinase Inhibitory Activity

Gourdain, Stéphanie; Dairou, Julien; Denhez, Clément; Bui, Linh‐Chi; Rodrigues‐Lima, Fernando; Janel, Nathalie; Delabar, Jean Maurice; Cariou, Kevin; Dodd, Robert H.

doi:10.1021/jm401049v

Cited by 60 publications

(51 citation statements)

References 58 publications

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“…Additionally, several inhibitors have been synthesized, such as Tg003 ( Muraki et al, 2004 ) and INDY ( Ogawa et al, 2010 ) two benzothiazole derivatives. For example, DANDY, a new 3,5-diaryl-7-azaindole that demonstrates potent inhibition against DYRK1A kinase activity ( Gourdain et al, 2013 ). HCD160 and its derivatives ( Kim N.D. et al, 2006 ; Koo et al, 2009 ), a series of substituted 6-arylquinazolin-4-amines ( Mott et al, 2009 ; Rosenthal et al, 2011 ), a new 3-(6-hydroxyindol-2-yl)-5-(phenyl)pyridine ( Kassis et al, 2011 ), a series of aryl-substituted aminopyrimidines ( Coombs et al, 2013 ), a new 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines ( Deau et al, 2013 ), an 8-arylpyrido[30′20′:4,5]thieno[3,2-d]pyrimidin-4-amines ( Loidreau et al, 2015 ), and a series of hydroxybenzothiophene ketones ( Smith et al, 2012 ; Schmitt et al, 2014 ).…”

Section: An Eruption Of Dyrk1a Kinase Inhibitorsmentioning

confidence: 99%

DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome

Duchon

Hérault

2016

Front. Behav. Neurosci.

152

143

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Down syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer’s disease (AD), leukemia, and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits. DYRK1A is a dual-specificity kinase that is overexpressed in DS and plays a key role in neurogenesis, outgrowth of axons and dendrites, neuronal trafficking and aging. Its pivotal role in the DS phenotype makes it a prime target for the development of therapeutics. Recently, disruption of DYRK1A has been found in Autosomal Dominant Mental Retardation 7 (MRD7), resulting in severe mental deficiency. Recent advances in the development of kinase inhibitors are expected, in the near future, to remove DS from the list of incurable diseases, providing certain conditions such as drug dosage and correct timing for the optimum long-term treatment. In addition the exact molecular and cellular mechanisms that are targeted by the inhibition of DYRK1A are still to be discovered.

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Section: An Eruption Of Dyrk1a Kinase Inhibitorsmentioning

confidence: 99%

DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome

Duchon

Hérault

2016

Front. Behav. Neurosci.

152

143

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“…New synthetic inhibitors of DYRK1A activity, with high purity and specificity, have been tested successfully showing recovery of cognition in DS mouse models (Gourdain et al, 2013;Falke et al, 2015;Kim et al, 2016;Neumann et al, 2018). Cognitive restoration with DYRK1A inhibitors was similar to the genetic rescue observed in in adult DS mouse models when one functional copy of…”

Section: Targeting Common Pathways Altered In Ds and Other Neurodevelmentioning

confidence: 66%

Translating molecular advances in Down syndrome and Fragile X syndrome into therapies

Faúndez

Toma

Bardoni

et al. 2018

European Neuropsychopharmacology

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Ongoing treatments for genetic developmental disorders of the central nervous system are mostly symptomatic and do not correct the genetic cause. Recent identification of common mechanisms between diseases has suggested that new therapeutic targets could be applied across intellectual disabilities with potential disease-modifying properties. The European Down syndrome and other genetic developmental disorders (DSG2D) network joined basic and clinical scientists to foster this research and carry out clinical trials. Here we discuss common mechanisms between several intellectual disabilities from genetic origin including Down's and Fragile X syndromes: i) how to model these complex diseases using neuronal cells and brain organoids derived from induced pluripotent stem cells; ii) how to integrate genomic, proteomic and interactome data to help defining common mechanisms and boundaries between diseases; iii) how to target common pathways for designing clinical trials and assessing their efficacy; iv) how to bring new neuro-therapies, such as noninvasive brain stimulations and cognitive training to clinical research. The basic and translational research efforts of the last years have utterly transformed our understanding of the molecular pathology of these diseases but much is left to be done to bring them to newborn babies and children to improve their quality of life.

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“…We recently reported that hydroxy derivatives of 3,5-diaryl-7-azaindoles (DANDYs) were potent, competitive inhibitors of DYRK1A 34 . The di-, tri- and tetrahydroxy diaryl azaindoles I - IV displayed in vitro inhibition of this kinase with IC 50 s in the 3 to 23 nM range (Fig.…”

Section: Introductionmentioning

confidence: 99%

DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives

Neumann

Gourdain

Albac

et al. 2018

Sci Rep

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Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20 mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS.

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Development of DANDYs, New 3,5-Diaryl-7-azaindoles Demonstrating Potent DYRK1A Kinase Inhibitory Activity

Cited by 60 publications

References 58 publications

DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome

DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome

Translating molecular advances in Down syndrome and Fragile X syndrome into therapies

DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives

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