Soluble 3′,6-Substituted Indirubins with Enhanced Selectivity toward Glycogen Synthase Kinase -3 Alter Circadian Period

Vougogiannopoulou, Konstantina; Ferandin, Yoan; Bettayeb, Karima; Myrianthopoulos, Vassilios; Lozach, Olivier; Fan, Yunzhen; Johnson, Carl Hirschie; Magiatis, Prokopios; Skaltsounis, Alexios‐Léandros; Mikros, Emmanuel; Meijer, Laurent

doi:10.1021/jm800648y

Cited by 109 publications

(106 citation statements)

References 48 publications

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“…4A) (16). In line with this, previous studies showed that application of GSK-3␤ inhibitors or its knockdown shortens the period length of cellular rhythms (19,40). Interestingly, Dyrk1a knockdown caused the effect of period shortening of ϳ0.5 h, although it advanced the accumulation timing of nuclear CRY2 as long as 2 to 4 h (Fig.…”

Section: Vol 30 2010supporting

confidence: 78%

DYRK1A and Glycogen Synthase Kinase 3β, a Dual-Kinase Mechanism Directing Proteasomal Degradation of CRY2 for Circadian Timekeeping

Kurabayashi

Hirota

Sakai

et al. 2010

Molecular and Cellular Biology

125

119

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Circadian molecular oscillation is generated by a transcription/translation-based feedback loop in which CRY proteins play critical roles as potent inhibitors for E-box-dependent clock gene expression. Although CRY2 undergoes rhythmic phosphorylation in its C-terminal tail, structurally distinct from the CRY1 tail, little is understood about how protein kinase(s) controls the CRY2-specific phosphorylation and contributes to the molecular clockwork. Here we found that Ser557 in the C-terminal tail of CRY2 is phosphorylated by DYRK1A as a priming kinase for subsequent GSK-3␤ (glycogen synthase kinase 3␤)-mediated phosphorylation of Ser553, which leads to proteasomal degradation of CRY2. In the mouse liver, DYRK1A kinase activity toward Ser557 of CRY2 showed circadian variation, with its peak in the accumulating phase of CRY2 protein.Knockdown of Dyrk1a caused abnormal accumulation of cytosolic CRY2, advancing the timing of a nuclear increase of CRY2, and shortened the period length of the cellular circadian rhythm. Expression of an S557A/S553A mutant of CRY2 phenocopied the effect of Dyrk1a knockdown in terms of the circadian period length of the cellular clock. DYRK1A is a novel clock component cooperating with GSK-3␤ and governs the Ser557 phosphorylation-triggered degradation of CRY2.

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Section: Vol 30 2010supporting

confidence: 78%

DYRK1A and Glycogen Synthase Kinase 3β, a Dual-Kinase Mechanism Directing Proteasomal Degradation of CRY2 for Circadian Timekeeping

Kurabayashi

Hirota

Sakai

et al. 2010

Molecular and Cellular Biology

125

119

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“…We screened 5,018 compounds from the Roscoff library including 588 purine derivatives (29) and 400 indirubin derivatives (30,31,32).…”

Section: Methodsmentioning

confidence: 99%

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

Durieu

Prina

Olivier

et al. 2016

Antimicrob Agents Chemother

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h Existing therapies for leishmaniases present significant limitations, such as toxic side effects, and are rendered inefficient by parasite resistance. It is of utmost importance to develop novel drugs targeting Leishmania that take these two limitations into consideration. We thus chose a target-based approach using an exoprotein kinase, Leishmania casein kinase 1.2 (LmCK1.2) that was recently shown to be essential for intracellular parasite survival and infectivity. We developed a four-step pipeline to identify novel selective antileishmanial compounds. In step 1, we screened 5,018 compounds from kinase-biased libraries with Leishmania and mammalian CK1 in order to identify hit compounds and assess their specificity. For step 2, we selected 88 compounds among those with the lowest 50% inhibitory concentration to test their biological activity on host-free parasites using a resazurin reduction assay and on intramacrophagic amastigotes using a high content phenotypic assay. Only 75 compounds showed antileishmanial activity and were retained for step 3 to evaluate their toxicity against mouse macrophages and human cell lines. The four compounds that displayed a selectivity index above 10 were then assessed for their affinity to LmCK1.2 using a target deconvolution strategy in step 4. Finally, we retained two compounds, PP2 and compound 42, for which LmCK1.2 seems to be the primary target. Using this four-step pipeline, we identify from several thousand molecules, two lead compounds with a selective antileishmanial activity.

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“…Their synthesis consists of two successive nucleophilic substitutions on the oxime (134). In a primary step, dibromoethane undergoes a first nucleophilic substitution by attack of the oxime in the presence of Et 3 N to form an intermediate (81).…”

Section: Novel Analogs Of 6biomentioning

confidence: 99%

A Colorful History: The Evolution of Indigoids

Gaboriaud‐Kolar

Nam

Skaltsounis

2014

Progress in the Chemistry of Organic Natural Products

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Soluble 3′,6-Substituted Indirubins with Enhanced Selectivity toward Glycogen Synthase Kinase -3 Alter Circadian Period

Cited by 109 publications

References 48 publications

DYRK1A and Glycogen Synthase Kinase 3β, a Dual-Kinase Mechanism Directing Proteasomal Degradation of CRY2 for Circadian Timekeeping

DYRK1A and Glycogen Synthase Kinase 3β, a Dual-Kinase Mechanism Directing Proteasomal Degradation of CRY2 for Circadian Timekeeping

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

A Colorful History: The Evolution of Indigoids

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