title: 5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer.
abstract: A series of 5-ureidobenzofuran-3-one indoles as potent inhibitors of PI3Kalpha and mTOR has been developed. The best potency in cells was obtained when the urea group was extended to a 4-[2-(dimethylamino)ethyl]methylamino amidophenyl group. A 7-fluoro group on the indole ring also enhanced cellular potency. Compound 18i, incorporating the optimal functional groups, showed high potency in cellular lines and was further studied in vivo. It was able to inhibit the biomarker phosphorylation for 8h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9.
authors.affiliation: Discovery Medicinal Chemistry, Wyeth Research, Pearl River, NY 10965, USA. zhangn@wyeth.com
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: James T
authors.initials: JT
authors.lastname: Anderson
authors.forename: Thai
authors.initials: T
authors.lastname: Nguyen
authors.forename: Sasmita
authors.initials: S
authors.lastname: Das
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Robert
authors.initials: R
authors.lastname: Mallon
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D047368:Tumor Burden / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C475670:2(3H)-benzofuranone; D001572:Benzofurans; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014508:Urea; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases