| Autor: |
Takeuchi CS; Department of Drug Discovery, Exelixis , 169 Harbor Way, South San Francisco, California 94083, USA., Kim BG, Blazey CM, Ma S, Johnson HW, Anand NK, Arcalas A, Baik TG, Buhr CA, Cannoy J, Epshteyn S, Joshi A, Lara K, Lee MS, Wang L, Leahy JW, Nuss JM, Aay N, Aoyama R, Foster P, Lee J, Lehoux I, Munagala N, Plonowski A, Rajan S, Woolfrey J, Yamaguchi K, Lamb P, Miller N |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2013 Mar 28; Vol. 56 (6), pp. 2218-34. Date of Electronic Publication: 2013 Mar 07. |
| DOI: |
10.1021/jm3007933 |
| Abstrakt: |
A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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