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.

Autor: Barlaam B; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Electronic address: bernard.barlaam2@astrazeneca.com., Cosulich S; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Delouvrié B; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Ellston R; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Fitzek M; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Germain H; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Green S; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Hancox U; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Harris CS; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Hudson K; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Lambert-van der Brempt C; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Lebraud H; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Magnien F; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Lamorlette M; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Le Griffon A; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Morgentin R; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Ouvry G; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Page K; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Pasquet G; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Polanska U; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Ruston L; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Saleh T; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Vautier M; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France., Ward L; AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Nov 15; Vol. 25 (22), pp. 5155-62. Date of Electronic Publication: 2015 Oct 09.
DOI: 10.1016/j.bmcl.2015.10.002
Abstrakt: 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 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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