Synthesis and identification of unprecedented selective inhibitors of CK1ε

Silveira-Dorta, Gastón; Sousa, Inês J.; Fernandes, Miguel X.; Martı́n, Victor S.; Padrón, José M.

doi:10.1016/j.ejmech.2015.03.046

Cited by 21 publications

(17 citation statements)

References 42 publications

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“…The in vitro antiproliferative activity of the synthesized compounds was measured against six human solid tumor cells, A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr (colon), using the sulforhodamine B assay [42,43]. The results were expressed as GI50, which is the drug concentration resulting in a 50% reduction of cellular net growth when compared with values of untreated control cells.…”

Section: Antiproliferative Activitymentioning

confidence: 99%

A green multicomponent synthesis of tocopherol analogues with antiproliferative activities

Ingold

Dapueto

Victoria

et al. 2018

European Journal of Medicinal Chemistry

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A one-pot efficient, practical and eco-friendly synthesis of tocopherol analogues has been developed using water or solvent free conditions via Passerini and Ugi multicomponent reactions. These reactions can be optimized using microwave irradiation or ultrasound as the energy source. Accordingly, a small library of 30 compounds was prepared for biological tests. The evaluation of the antiproliferative activity in the human solid tumor cell lines A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast), and WiDr (colon) provided lead compounds with GI values between 1 and 5 μM. A structure-activity relationship is also discussed. One of the studied compounds comes up as a future candidate for the development of potent tocopherol-mimetic therapeutic agents for cancer.

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Section: Antiproliferative Activitymentioning

confidence: 99%

A green multicomponent synthesis of tocopherol analogues with antiproliferative activities

Ingold

Dapueto

Victoria

et al. 2018

European Journal of Medicinal Chemistry

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“…The same approach might aid to discard targets without the need of testing them individually [1]. The combination of phenotypic data with computational methods represents another alternative that we have explored with success [3].…”

Section: Discussionmentioning

confidence: 99%

“…The lead compound, named DTA0100, was selected for further biological evaluation. Further studies suggested that their anti-proliferative activity is not chiral-dependent and docking studies reinforced that they act as catalytic inhibitors of the nuclear enzyme TOP2 [3]. In a recent study, DTA0100 was tagged with dansyl to generate fluorescently-labeled DTA0100 (dns-DTA0100).…”

Section: Introductionmentioning

confidence: 99%

A Small Molecule Tubulin Depolymerizing Agent Identiﬁed by a Phenotypic Drug Discovery Approach

2018

J. Mol. Clin. Med.

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In the scenario of drug discovery, numerous in vitro testing initiatives had been established. Thus far, no general methodology is reputable and literature on this hot topic is scarce. In this respect, we propose a strategy based on a Phenotypic Drug Discovery approach. Within our program directed at the discovery of new antitumor agents, we have focused our attention on compounds that disturb the cell cycle. Our strategy relies on the use of a set of biological assays organized in a modular fashion. Herein, we exemplified this strategy with a family of propargylic enol ether derivatives. Using different assays in sequential stages and in a stepwise manner, our studies allowed us to understand the bioactivity of this family of compounds and led us to identify tubulin as the main molecular target.

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“…This makes it difficult to find selectivity towards a given isoform. In fact, the literature describes only two selective inhibitors of CK1ε (ICK1ε), GSD0054 [35,36] and PF-4800567 [37]; as well as two selective inhibitors of CK1δ (ICK1δ ), SR-3029 [38] and LH846 [39] (Table 2). All the other reported compounds behave mainly as dual CK1δ /ε inhibitors (ICK1δ /ε).…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

“…The hypothesis that CK1ε mediates activities of circadian rhythm gene products and β -catenin through independent mechanisms, might possibly explain the observed effects [29]. The second molecule reported as a selective ICK1ε is GSD0054, which behaves as a selective CK1ε inhibitor in enzymatic assays [35]. This small molecule does not interact with other kinases, as demonstrated with the DiscoverRX [36].…”

Section: Selective Inhibitors Of Ck1εmentioning

confidence: 99%

Facts and myths of selective casein kinase 1ε einhibition

2018

J. Mol. Clin. Med.

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In the scenario of drug discovery, the challenge is to fully understand and elucidate the mechanism of action to identify, with high resolution, the molecular determinant(s) targeted by the drug and responsible for its pharmacological activity. Cancer offers scientists an almost infinite arena of signaling pathways, targets and small molecules for therapeutic intervention. Among the multiple chemotherapeutic strategies to combat cancer, synthetic lethality remains underexplored. Casein kinase 1 ε (CK1ε) is a serine/threonine protein kinase that has been described as a synthetic lethal partner of the Wnt/β-catenin signaling pathway. Despite its potential as a desirable therapeutic target, only two selective inhibitors are available: PF-4800567 and GSD0054. Until the discovery of GSD0054, CK1ε inhibitors have been considered candidate drugs exclusively in psychopharmacology. In this review, we focus on three key points which we consider essential to define the scope of CK1ε as a synthetic lethal partner and its inhibitors as chemotherapeutics: the therapeutic relevance of this kinase, the scarce availability of selective inhibitors (due to the high homology with its sibling isoform CK1δ), and the constraint of existing computational tools. This paper represents the first review covering the potential of CK1ε as a druggable target for cancer treatment.

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Synthesis and identification of unprecedented selective inhibitors of CK1ε

Cited by 21 publications

References 42 publications

A green multicomponent synthesis of tocopherol analogues with antiproliferative activities

A green multicomponent synthesis of tocopherol analogues with antiproliferative activities

A Small Molecule Tubulin Depolymerizing Agent Identiﬁed by a Phenotypic Drug Discovery Approach

Facts and myths of selective casein kinase 1ε einhibition

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