5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer.
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.
Zhang
Nan
N
Discovery Medicinal Chemistry, Wyeth Research, Pearl River, NY 10965, USA. zhangn@wyeth.com
Ayral-Kaloustian
Semiramis
S
Anderson
James T
JT
Nguyen
Thai
T
Das
Sasmita
S
Venkatesan
Aranapakam M
AM
Brooijmans
Natasja
N
Lucas
Judy
J
Yu
Ker
K
Hollander
Irwin
I
Mallon
Robert
R
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
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