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Br J Haematol ; 150(1): 46-57, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20507304


Constitutive activation of Janus kinase (Jak) 2 is the most prevalent pathogenic event observed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove valuable in their management. Inhibition of the Aurora kinases has also proven to be an effective therapeutic strategy in a number of haematological malignancies. AT9283 is a multi-targeted kinase inhibitor with potent activity against Jak2 and Aurora kinases A and B, and is currently being evaluated in clinical trials. To investigate the therapeutic potential of AT9283 in the MPD we studied its activity in a number of Jak2-dependent systems. AT9283 potently inhibited proliferation and Jak2-related signalling in Jak2-dependent cell lines as well as inhibiting the formation of erythroid colonies from haematopoietic progenitors isolated from MPD patients with Jak2 mutations. The compound also demonstrated significant therapeutic potential in vivo in an ETV6-JAK2 (TEL-JAK2) murine leukaemia model. Inhibition of both Jak2 and Aurora B was observed in the model systems used, indicating a dual mechanism of action. Our results suggest that AT9283 may be a valuable therapy in patients with MPD and that the dual inhibition of Jak2 and the Aurora kinases may potentially offer combinatorial efficacy in the treatment of these diseases.

Antineoplásicos/farmacología , Bencimidazoles/farmacología , Janus Quinasa 2/antagonistas & inhibidores , Trastornos Mieloproliferativos/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Antineoplásicos/uso terapéutico , Aurora Quinasa B , Aurora Quinasas , Bencimidazoles/uso terapéutico , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Células Precursoras Eritroides/efectos de los fármacos , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/fisiología , Leucemia Experimental/tratamiento farmacológico , Leucemia Experimental/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Urea/farmacología , Urea/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
J Med Chem ; 52(2): 379-88, 2009 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-19143567


Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.

Bencimidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , Bencimidazoles/química , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Urea/química , Urea/farmacocinética , Urea/farmacología