- Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers
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Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kβ and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25 mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.
- Barlaam, Bernard,Cosulich, Sabina,Delouvrié, Bénédicte,Ellston, Rebecca,Fitzek, Martina,Germain, Hervé,Green, Stephen,Hancox, Urs,Harris, Craig S.,Hudson, Kevin,Lambert-Van Der Brempt, Christine,Lebraud, Honorine,Magnien, Fran?oise,Lamorlette, Maryannick,Le Griffon, Antoine,Morgentin, Rémy,Ouvry, Gilles,Page, Ken,Pasquet, Georges,Polanska, Urszula,Ruston, Linette,Saleh, Twana,Vautier, Michel,Ward, Lara
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- CHEMICAL COMPOUNDS
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The invention concerns compounds of Formula (I) or pharmaceutically-acceptable salts thereof, wherein R1 and R2 have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.
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Paragraph 0568; 0570; 0571
(2014/08/06)
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- CHEMICAL COMPOUNDS
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The invention concerns compounds of Formula (I) (Formula (I)) or pharmaceutically-acceptable salts thereof, wherein R1 and R2 have any of the meanings defined herein before in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.
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Page/Page column 111; 112
(2014/08/07)
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- CHEMICAL COMPOUNDS
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The invention concerns compounds of Formula (I) or pharmaceutically-acceptable salts thereof, wherein R1 to R5 have any of the meanings defined hereinbefore in the description: processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.
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Paragraph 0569
(2014/12/09)
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- Compounds Useful as Inhibitors of ATR Kinase
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The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, a
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Paragraph 0240; 0242
(2013/05/21)
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- AMINOPYRAZINE COMPOUNDS USEFUL AS INHIBITORS OF TRA KINASE
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The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula (I): wherein the variables are as defined herein.
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Page/Page column 76-77
(2012/10/18)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula I wherein the variables are as defined herein.
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Page/Page column 50
(2011/12/02)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present disclosure relates to pyrazine compounds of formula (I) wherein L, n, R1, and R2 are as described in the specification. These compounds are useful as inhibitors of ATR protein kinase. The disclosure also relates to pharmaceutically acceptable compositions comprising the compounds of the disclosure; methods of treating of various diseases, disorders, and conditions using the compounds of the disclosure; processes for preparing the compounds of the disclosure; intermediates for the preparation of the compounds of the disclosure; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.
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Page/Page column 144
(2010/06/11)
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