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Ref Type Journal Article
PMID (23394126)
Authors Takeuchi CS, 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
Title Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR).
Journal Vol Issue Date Pages Journal Short Title
Journal of medicinal chemistry 56 6 2013 Mar 28 2218-34 J Med Chem
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
XL388 XL388 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
XL388 XL-388|XL 388 mTOR Inhibitor 51 XL388 is a selective ATP-competitive mTOR inhibitor that inhibits mTORC1 and mTORC2, resulting in decreased activation of downstream targets and potentially leading to decreased tumor growth (PMID: 23394126, PMID: 28404914, PMID: 27385099).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References