title: Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR).
abstract: 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.
authors: Department of Drug Discovery, Exelixis , 169 Harbor Way, South San Francisco, California 94083, USA.
authors: Craig S
authors: CS
authors: Takeuchi
authors: Byung Gyu
authors: BG
authors: Kim
authors: Charles M
authors: CM
authors: Blazey
authors: Sunghoon
authors: S
authors: Ma
authors: Henry W B
authors: HW
authors: Johnson
authors: Neel K
authors: NK
authors: Anand
authors: Arlyn
authors: A
authors: Arcalas
authors: Tae Gon
authors: TG
authors: Baik
authors: Chris A
authors: CA
authors: Buhr
authors: Jonah
authors: J
authors: Cannoy
authors: Sergey
authors: S
authors: Epshteyn
authors: Anagha
authors: A
authors: Joshi
authors: Katherine
authors: K
authors: Lara
authors: Matthew S
authors: MS
authors: Lee
authors: Longcheng
authors: L
authors: Wang
authors: James W
authors: JW
authors: Leahy
authors: John M
authors: JM
authors: Nuss
authors: Naing
authors: N
authors: Aay
authors: Ron
authors: R
authors: Aoyama
authors: Paul
authors: P
authors: Foster
authors: Jae
authors: J
authors: Lee
authors: Isabelle
authors: I
authors: Lehoux
authors: Narsimha
authors: N
authors: Munagala
authors: Arthur
authors: A
authors: Plonowski
authors: Sharmila
authors: S
authors: Rajan
authors: John
authors: J
authors: Woolfrey
authors: Kyoko
authors: K
authors: Yamaguchi
authors: Peter
authors: P
authors: Lamb
authors: Nicole
authors: N
authors: Miller
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D048588:Benzoxazines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001682:Biological Availability; D045744:Cell Line, Tumor; D004285:Dogs; D055808:Drug Discovery; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D048588:Benzoxazines; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D058570:TOR Serine-Threonine Kinases