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1.
J Enzyme Inhib Med Chem ; 35(1): 1840-1853, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33040634

RESUMEN

Haspin is a mitotic protein kinase required for proper cell division by modulating Aurora B kinase localisation and activity as well as histone phosphorylation. Here a series of imidazopyridazines based on the CHR-6494 and Structure Activity Relationship was established. An assessment of the inhibitory activity of the lead structures on human Haspin and several other protein kinases is presented. The lead structure was rapidly optimised using a combination of crystal structures and effective docking models, with the best inhibitors exhibiting potent inhibitory activity on Haspin with IC50 between 6 and 100 nM in vitro. The developed inhibitors displayed anti-proliferative properties against various human cancer cell lines in 2D and spheroid cultures and significantly inhibited the migration ability of osteosarcoma U-2 OS cells. Notably, we show that our lead compounds are powerful Haspin inhibitors in human cells, and did not block G2/M cell cycle transition due to improved selectivity against CDK1/CyclinB.


Asunto(s)
Antineoplásicos/síntesis química , Neoplasias Óseas/tratamiento farmacológico , Indazoles/síntesis química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Osteosarcoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridazinas/síntesis química , Secuencia de Aminoácidos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteína Quinasa CDC2/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina B/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Histonas/química , Humanos , Indazoles/farmacología , Simulación del Acoplamiento Molecular , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/farmacología , Relación Estructura-Actividad
2.
Cells ; 9(4)2020 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-32272587

RESUMEN

The sea urchin embryo provides a valuable system to analyse the molecular mechanisms orchestrating cell cycle progression and mitosis in a developmental context. However, although it is known that the regulation of histone activity by post-translational modification plays an important role during cell division, the dynamics and the impact of these modifications have not been characterised in detail in a developing embryo. Using different immuno-detection techniques, we show that the levels of Histone 3 phosphorylation at Threonine 3 oscillate in synchrony with mitosis in Sphaerechinus granularis early embryos. We present, in addition, the results of a pharmacological study aimed at analysing the role of this key histone post-translational modification during sea urchin early development.


Asunto(s)
Erizos de Mar/metabolismo , Animales , División Celular/fisiología , Histonas/metabolismo , Mitosis/fisiología , Fosforilación , Erizos de Mar/citología , Erizos de Mar/embriología
3.
Mar Drugs ; 17(10)2019 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-31600933

RESUMEN

Regulated cell death (RCD) results from the activation of one or more signal transduction modules both in physiological or pathological conditions. It is now established that RCD is involved in numerous human diseases, including cancer. As regulated cell death processes can be modulated by pharmacological tools, the research reported here aims to characterize new marine compounds acting as RCD modulators. Protein kinases (PKs) are key signaling actors in various RCDs notably through the control of either mitosis (e.g., the PKs Aurora A and B) or necroptosis (e.g., RIPK1 and RIPK3). From the primary screening of 27 various extracts of marine organisms collected in the Mediterranean Sea, an extract and subsequently a purified high molecular weight compound dubbed P3, were isolated from the marine sponge Crambe tailliezi and characterized as a selective inhibitor of PKs Aurora A and B. Furthermore, P3 was shown to induce apoptosis and to decrease proliferation and mitotic index of human osteosarcoma U-2 OS cells.


Asunto(s)
Productos Biológicos/farmacología , Crambe (Esponja)/química , Crambe (Esponja)/metabolismo , Citotoxinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HEK293 , Células Hep G2 , Humanos , Células MCF-7 , Mar Mediterráneo , Peso Molecular , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos
4.
J Cell Sci ; 132(21)2019 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-31601613

RESUMEN

Timely and precise control of Aurora B kinase, the chromosomal passenger complex (CPC) catalytic subunit, is essential for accurate chromosome segregation and cytokinesis. Post-translational modifications of CPC subunits are directly involved in controlling Aurora B activity. Here, we identified a highly conserved acidic STD-rich motif of INCENP that is phosphorylated during mitosis in vivo and by Plk1 in vitro and is involved in controlling Aurora B activity. By using an INCENP conditional-knockout cell line, we show that impairing the phosphorylation status of this region disrupts chromosome congression and induces cytokinesis failure. In contrast, mimicking constitutive phosphorylation not only rescues cytokinesis but also induces ectopic furrows and contractile ring formation in a Plk1- and ROCK1-dependent manner independent of cell cycle and microtubule status. Our experiments identify the phospho-regulation of the INCENP STD motif as a novel mechanism that is key for chromosome alignment and cytokinesis.This article has an associated First Person interview with the first author of the paper.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Ciclo Celular/fisiología , Microtúbulos/metabolismo , Mutación/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas/metabolismo , Citocinesis/fisiología , Humanos , Mitosis/fisiología , Quinasas Asociadas a rho/metabolismo , Quinasa Tipo Polo 1
5.
Mar Drugs ; 17(2)2019 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-30717235

RESUMEN

The marine α-pyrone macrolide neurymenolide A was previously isolated from the Fijian red macroalga, Neurymenia fraxinifolia, and characterized as an antibacterial agent against antibiotic-resistant strains that also exhibited moderate cytotoxicity in vitro against cancer cell lines. This compound was also shown to exhibit allelopathic effects on Scleractinian corals. However, to date no mechanism of action has been described in the literature. The present study showed, for the first time, the isolation of neurymenolide A from the New Caledonian Rhodophyta, Phacelocarpus neurymenioides. We confirmed the compound's moderate cytotoxicity in vitro against several human cell lines, including solid and hematological malignancies. Furthermore, we combined fluorescence microscopy and flow cytometry to demonstrate that treatment of U-2 OS osteosarcoma human cells with neurymenolide A could block cell division in prometaphase by inhibiting the correct formation of the mitotic spindle, which induced a mitotic catastrophe that led to necrosis and apoptosis. Absolute configuration of the stereogenic center C-17 of neurymenolide A was deduced by comparison of the experimental and theoretical circular dichroism spectra. Since the total synthesis of this compound has already been described, our findings open new avenues in cancer treatment for this class of marine molecules, including a new source for the natural product.


Asunto(s)
Macrólidos/química , Macrólidos/farmacología , Pironas/química , Pironas/farmacología , Rhodophyta/química , Huso Acromático/efectos de los fármacos , Apoptosis/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Células K562 , Células MCF-7 , Microtúbulos/patología , Mitosis/efectos de los fármacos , Necrosis/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología
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