ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)
英文:
ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)
著者
和文:
TAKEUCHI CRAIG,
Byung Gyu Kim,
Charles M. Blazey,
Sunghoon Ma,
Henry W. B. Johnson,
Neel K. Anand,
Arlyn Arcalas,
Tae Gon Baik,
Chris A. Buhr,
Jonah Cannoy,
Sergey Epshteyn,
Anagha Joshi,
Katherine Lara,
Matthew S. Lee,
Longcheng Wang,
James W. Leahy,
John M. Nuss,
Naing Aay,
Ron Aoyama,
Paul Foster,
Jae Lee,
Isabelle Lehoux,
Narsimha Munagala,
Arthur Plonowski,
Sharmila Rajan,
John Woolfrey,
Kyoko Yamaguchi,
Peter Lamb,
Nicole Miller.
英文:
Craig Takeuchi,
Byung Gyu Kim,
Charles M. Blazey,
Sunghoon Ma,
Henry W. B. Johnson,
Neel K. Anand,
Arlyn Arcalas,
Tae Gon Baik,
Chris A. Buhr,
Jonah Cannoy,
Sergey Epshteyn,
Anagha Joshi,
Katherine Lara,
Matthew S. Lee,
Longcheng Wang,
James W. Leahy,
John M. Nuss,
Naing Aay,
Ron Aoyama,
Paul Foster,
Jae Lee,
Isabelle Lehoux,
Narsimha Munagala,
Arthur Plonowski,
Sharmila Rajan,
John Woolfrey,
Kyoko Yamaguchi,
Peter Lamb,
Nicole Miller.
A series of novel, highly potent, selective, and ATP-competitivemammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffoldhave been identified. Lead optimization resulted in the discovery of inhibitors with lownanomolar activity and greater than 1000-fold selectivity over the closely related PI3Kkinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates.Furthermore, this compound displayed good pharmacokinetics and oral exposure inmultiple species with moderate bioavailability. Oral administration of compound 28 toathymic nude mice implanted with human tumor xenografts afforded significant anddose-dependent antitumor activity.
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