title: Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR).
abstract: We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.
authors.affiliation: Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States. tsouh@wyeth.com
authors.forename: Hwei-Ru
authors.initials: HR
authors.lastname: Tsou
authors.forename: Gloria
authors.initials: G
authors.lastname: MacEwan
authors.forename: Gary
authors.initials: G
authors.lastname: Birnberg
authors.forename: George
authors.initials: G
authors.lastname: Grosu
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Bursavich
authors.forename: Joel
authors.initials: J
authors.lastname: Bard
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.forename: Lourdes
authors.initials: L
authors.lastname: Toral-Barza
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D001572:Benzofurans; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse